Publications

Smoothened variants explain the majority of drug resistance in Basal cell carcinoma. Cancer cell
Atwood, S.X., Sarin, K.Y., Whitson, R.J., Li, J.R., Kim, G., Rezaee, M., Ally, M.S., Kim, J., Yao, C., Chang, A. L., Oro, A. E., Tang, J.Y., 
2015; 27 (3): 342-353  More 

Abstract

Advanced basal cell carcinomas (BCCs) frequently acquire resistance to Smoothened (SMO) inhibitors through unknown mechanisms. Here we identify SMO mutations in 50% (22 of 44) of resistant BCCs and show that these mutations maintain Hedgehog signaling in the presence of SMO inhibitors. Alterations include four ligand binding pocket mutations defining sites of inhibitor binding and four variants conferring constitutive activity and inhibitor resistance, illuminating pivotal residues that ensure receptor autoinhibition. In the presence of a SMO inhibitor, tumor cells containing either class of SMO mutants effectively outcompete cells containing the wild-type SMO. Finally, we show that both classes of SMO variants respond to aPKC-ι/λ or GLI2 inhibitors that operate downstream of SMO, setting the stage for the clinical use of GLI antagonists.

View details for DOI 10.1016/j.ccell.2015.02.002

View details for PubMedID 25759020

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Genomic analysis of smoothened inhibitor resistance in Basal cell carcinoma. Cancer cell
Sharpe, H. J., Pau, G., Dijkgraff, G. J., Basset-Seguin, N., Modrusan, Z., Januario, T., Tsui, V., Durham, A. B., Dlugosz, A. A., Haverty, P. M.,
Bourgon, R., Tang, J. Y., Sarin, K. Y., Dirix, L., Fisher, D. C., Rudin, C. M., Sofen, H., Migden, M. R., Yauch, R. L., de Sauvage, F. J.
2015; 27(3): 327-341 More 

Abstract

Smoothened (SMO) inhibitors are under clinical investigation for the treatment of several cancers. Vismodegib is approved for the treatment of locally advanced and metastatic basal cell carcinoma (BCC). Most BCC patients experience significant clinical benefit on vismodegib, but some develop resistance. Genomic analysis of tumor biopsies revealed that vismodegib resistance is associated with Hedgehog (Hh) pathway reactivation, predominantly through mutation of the drug target SMO and to a lesser extent through concurrent copy number changes in SUFU and GLI2. SMO mutations either directly impaired drug binding or activated SMO to varying levels. Furthermore, we found evidence for intra-tumor heterogeneity, suggesting that a combination of therapies targeting components at multiple levels of the Hh pathway is required to overcome resistance.

View details for DOI 10.1016/j.ccell.2015.02.001

View details for PubMedID 25759019

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Open-Label, Exploratory Phase II Trial of Oral Itraconazole for the Treatment of Basal Cell Carcinoma. JOURNAL OF CLINICAL ONCOLOGY
Kim, D. J., Kim, J., Spaunhurst, K., Montoya, J., Khodosh, R., Chandra, K., Fu, T., Gilliam, A., Molgo, M., Beachy, P. A., Tang, J. Y.
2014; 32 (8): 745-751 More 

Abstract

Itraconazole, a US Food and Drug Administration-approved antifungal drug, inhibits the Hedgehog (HH) signaling pathway, a crucial driver of basal cell carcinoma (BCC) tumorigenesis, and reduces BCC growth in mice. We assessed the effect of itraconazole on the HH pathway and on tumor size in human BCC tumors.Patients with ≥ one BCC tumor > 4 mm in diameter were enrolled onto two cohorts to receive oral itraconazole 200 mg twice per day for 1 month (cohort A) or 100 mg twice per day for an average of 2.3 months (cohort B). The primary end point was change in biomarkers: Ki67 tumor proliferation and HH activity (GLI1 mRNA). Secondary end points included change in tumor size in a subset of patients with multiple tumors.A total of 29 patients were enrolled, of whom 19 were treated with itraconazole. Itraconazole treatment was associated with two adverse events (grade 2 fatigue and grade 4 congestive heart failure). Itraconazole reduced cell proliferation by 45% (P = .04), HH pathway activity by 65% (P = .03), and reduced tumor area by 24% (95% CI, 18.2% to 30.0%). Of eight patients with multiple nonbiopsied tumors, four achieved partial response, and four had stable disease. Tumors from untreated control patients and from those previously treated with vismodegib showed no significant changes in proliferation or tumor size.Itraconazole has anti-BCC activity in humans. These results provide the basis for larger trials of longer duration to measure the clinical efficacy of itraconazole, especially relative to other HH pathway inhibitors.

View details for DOI 10.1200/JCO.2013.49.9525

View details for Web of Science ID 000332483400010

View details for PubMedID 24493717

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Itraconazole and Arsenic Trioxide Inhibit Hedgehog Pathway Activation and Tumor Growth Associated with Acquired Resistance to Smoothened Antagonists. CANCER CELL
Kim, J., Aftab, B. T., Tang, J. Y., Kim, D., Lee, A. H., Rezaee, M., Kim, J., Chen, B., King, E. M., Borodovsky, A., Riggins, G. J., Epstein, E. H.,
Beachy, P. A., Rudin, C. M. 2013; 23 (1): 23-34  More 

Abstract

Recognition of the multiple roles of Hedgehog signaling in cancer has prompted intensive efforts to develop targeted pathway inhibitors. Leading inhibitors in clinical development act by binding to a common site within Smoothened, a critical pathway component. Acquired Smoothened mutations, including SMO(D477G), confer resistance to these inhibitors. Here, we report that itraconazole and arsenic trioxide, two agents in clinical use that inhibit Hedgehog signaling by mechanisms distinct from that of current Smoothened antagonists, retain inhibitory activity in vitro in the context of all reported resistance-conferring Smoothened mutants and GLI2 overexpression. Itraconazole and arsenic trioxide, alone or in combination, inhibit the growth of medulloblastoma and basal cell carcinoma in vivo, and prolong survival of mice with intracranial drug-resistant SMO(D477G) medulloblastoma.

View details for DOI 10.1016/j.ccr.2012.11.017

View details for Web of Science ID 000313759100005

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Inhibiting the Hedgehog Pathway in Patients with the Basal-Cell Nevus Syndrome  NEW ENGLAND JOURNAL OF MEDICINE
Tang, J. Y., Mackay-Wiggan, J. M., Aszterbaum, M., Yauch, R. L., Lindgren, J., Chang, K., Coppola, C., Chanana, A. M., Marji, J., Bickers, D. R.,
Epstein, E. H. 2012; 366 (23): 2180-2188  More 

Abstract

Dysregulated hedgehog signaling is the pivotal molecular abnormality underlying basal-cell carcinomas. Vismodegib is a new orally administered hedgehog-pathway inhibitor that produces objective responses in locally advanced and metastatic basal-cell carcinomas.We tested the anti-basal-cell carcinoma efficacy of vismodegib in a randomized, double-blind, placebo-controlled trial in patients with the basal-cell nevus syndrome at three clinical centers from September 2009 through January 2011. The primary end point was reduction in the incidence of new basal-cell carcinomas that were eligible for surgical resection (surgically eligible) with vismodegib versus placebo after 3 months; secondary end points included reduction in the size of existing basal-cell carcinomas.In 41 patients followed for a mean of 8 months (range, 1 to 15) after enrollment, the per-patient rate of new surgically eligible basal-cell carcinomas was lower with vismodegib than with placebo (2 vs. 29 cases per group per year, P<0.001), as was the size (percent change from baseline in the sum of the longest diameter) of existing clinically significant basal-cell carcinomas (-65% vs. -11%, P=0.003). In some patients, all basal-cell carcinomas clinically regressed. No tumors progressed during treatment with vismodegib. Patients receiving vismodegib routinely had grade 1 or 2 adverse events of loss of taste, muscle cramps, hair loss, and weight loss. Overall, 54% of patients (14 of 26) receiving vismodegib discontinued drug treatment owing to adverse events. At 1 month, vismodegib use had reduced the hedgehog target-gene expression by basal-cell carcinoma by 90% (P<0.001) and diminished tumor-cell proliferation, but apoptosis was not affected. No residual basal-cell carcinoma was detectable in 83% of biopsy samples taken from sites of clinically regressed basal-cell carcinomas.Vismodegib reduces the basal-cell carcinoma tumor burden and blocks growth of new basal-cell carcinomas in patients with the basal-cell nevus syndrome. The adverse events associated with treatment led to discontinuation in over half of treated patients. (Funded by Genentech and others; ClinicalTrials.gov number, NCT00957229.).

View details for Web of Science ID 000304863400007

View details for PubMedID 22670904

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Aspirin is associated with lower melanoma risk among postmenopausal Caucasian women: the Women's Helath Initiative. 
Gamba CA, Swetter SM, Stefanick ML, Kubo J, Desai M, Spaunhurst KM, Sinha AA, Asgari MM, Sturgeon S, Tang JY.
Cancer. 2013; 119 (8): 1562-9  More 

              Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been associated with decreased risk of gastric, colorectal, and breast cancer. However, the impact of NSAIDs on risk of melanoma has been inconsistent. We evaluated the association between NSAID use and cutaneous melanoma risk in the WHI Observational Study (WHI OS). At study entry, use of aspirin (ASA) and non-aspirin NSAIDs was assessed among 59,806 postmenopausal Caucasian women aged 50 to 79. We used Cox proportional hazards models after adjusting for participant skin type, sun exposure history, and medical indications for NSAID use among other confounders. During a median follow-up of 12 years, 548 incident melanomas were confirmed by medical review. Women who used ASA had a 21% lower risk of melanoma (HR: 0.79, 95% CI: 0.63-0.98) relative to non-users. Increased duration of ASA use (<1 year, 1-4 years, and ≥5 years) was associated with an 11% lower risk of melanoma for each categorical increase (ptrend=0.01), and women with ≥5 years use had a 30% lower melanoma risk (HR 0.70, 95% CI: 0.55-0.94). In contrast, use of non-ASA NSAIDs and acetaminophen were not associated with melanoma risk. Postmenopausal women who used ASA had a significantly lower risk of melanoma, with longer duration of ASA use associated with greater protection. Although this study is limited by the observational design and self-report of NSAID use, these findings suggest that ASA may have a chemopreventive effect against the development of melanoma and warrant further clinical investigation.

View details for DOI  10.1002/cncr.27817

View details for PubMedID 22670904

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GLI activation by atypical protein kinase C ι/λ regulates the growth of basal cell carcinomas.
Atwood SX, Li M, Lee A, Tang JY, Oro AE.
Nature. 2013; 494 (7438): 484-8  More 

              Abstract

Growth of basal cell carcinomas (BCCs) requires high levels of hedgehog (HH) signalling through the transcription factor GLI. Although inhibitors of membrane protein smoothened (SMO) effectively suppress HH signalling, early tumour resistance illustrates the need for additional downstream targets for therapy. Here we identify atypical protein kinase C ι/λ (aPKC-ι/λ) as a novel GLI regulator in mammals. aPKC-ι/λ and its polarity signalling partners co-localize at the centrosome and form a complex with missing-in-metastasis (MIM), a scaffolding protein that potentiates HH signalling. Genetic or pharmacological loss of aPKC-ι/λ function blocks HH signalling and proliferation of BCC cells. Prkci is a HH target gene that forms a positive feedback loop with GLI and exists at increased levels in BCCs. Genome-wide transcriptional profiling shows that aPKC-ι/λ and SMO control the expression of similar genes in tumour cells. aPKC-ι/λ functions downstream of SMO to phosphorylate and activate GLI1, resulting in maximal DNA binding and transcriptional activation. Activated aPKC-ι/λ is upregulated in SMO-inhibitor-resistant tumours and targeting aPKC-ι/λ suppresses signalling and growth of resistant BCC cell lines. These results demonstrate that aPKC-ι/λ is critical for HH-dependent processes and implicates aPKC-ι/λ as a new, tumour-selective therapeutic target for the treatment of SMO-inhibitor-resistant cancers.

View details for DOI 10.1038/nature11889

View details for PubMedID 22670904

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Calcium plus vitamin D supplementation and the risk of nonmelanoma and melanoma skin cancer: post hoc analyses of the women's helath initiative randomized controlled trial.
Tang JY, Fu T, Leblanc E, Manson JE, Feldman D, Linos E, Vitolins MZ, Zeitouni NC, Larson J, Stefanick ML.
J Clin Oncol. 2011; 29 (22): 3078-84  More 

              Abstract

In light of inverse relationships reported in observational studies of vitamin D intake and serum 25-hydroxyvitamin D levels with risk of nonmelanoma skin cancer (NMSC) and melanoma, we evaluated the effects of vitamin D combined with calcium supplementation on skin cancer in a randomized placebo-controlled trial. Postmenopausal women age 50 to 79 years (N = 36,282) enrolled onto the Women's Health Initiative (WHI) calcium/vitamin D clinical trial were randomly assigned to receive 1,000 mg of elemental calcium plus 400 IU of vitamin D3 (CaD) daily or placebo for a mean follow-up period of 7.0 years. NMSC and melanoma skin cancers were ascertained by annual self-report; melanoma skin cancers underwent physician adjudication. Neither incident NMSC nor melanoma rates differed between treatment (hazard ratio [HR], 1.02; 95% CI, 0.95 to 1.07) and placebo groups (HR, 0.86; 95% CI, 0.64 to 1.16). In subgroup analyses, women with history of NMSC assigned to CaD had a reduced risk of melanoma versus those receiving placebo (HR, 0.43; 95% CI, 0.21 to 0.90; P(interaction) = .038), which was not observed in women without history of NMSC. Vitamin D supplementation at a relatively low dose plus calcium did not reduce the overall incidence of NMSC or melanoma. However, in women with history of NMSC, CaD supplementation reduced melanoma risk, suggesting a potential role for calcium and vitamin D supplements in this high-risk group. Results from this post hoc subgroup analysis should be interpreted with caution but warrant additional investigation.

View details for DOI 10.1200/JCO.2011.34.5967

View details for PubMedID 22670904

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Comment on Basal Cell Carcinoma Rebound After Cessation of Vismodegib in an Individual With Basal Cell Nevus Syndrome.
Ally MS, Wysong A, Tang JY, Aasi S.
Dermatol Surg. 2013   More 

                  Abstract

    View details for DOI 10.1111/j.1524-4725.2012.02513.x

    View details for PubMedID 22805146

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Cutaneous human papillomavirus infection and Basal cell carcinoma of the skin.
Ally MS, Tang JY, Arron ST.
J Invest Dermatol. 2013; 133 (6): 1456-8  More 

Abstract

Human papillomavirus (HPV) is ubiquitous in skin and has been associated with nonmelanoma skin cancer. Iannacone et al. investigate the role of HPV in basal cell carcinoma (BCC) by assessing the presence of HPV antibodies, HPV DNA in tumors, and the relationship between these two markers and BCC. In contrast to squamous cell carcinoma (SCC), there is no association between HPV and BCC.

View details for DOI 10.1038/jid.2013.46

View details for PubMedID 23673499

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Factors affecting sunscreen use and sun avoidance in a U.S. national sample of organ transplant recipients.
Mihalis EL, Wysong A, Boscardin WJ, Tang JY, Chren MM, Arron ST.
Br J Dermatol. 2013; 168 (2): 346-53  More 

              Abstract

Organ transplant recipients have an increased risk of nonmelanoma skin cancers due to immunosuppressive therapy following transplantation. Use of sunscreen has been shown to reduce this risk. To identify patient and healthcare factors associated with sun-protective behaviours in organ transplant recipients after transplantation with the goal of increasing overall sunscreen use. This study utilized a cross-sectional, retrospective survey from a national sample of 198 organ transplant recipients in the U.S.A. from 2004 to 2008 with no prior diagnosis of skin cancer. The main outcome measures were sunscreen use and sun avoidance before and after transplantation. Frequency of sunscreen use and sun exposure was obtained by self-report on Likert scales ranging from never to always, and these responses were converted to a numerical scale from 0 to 4. Overall sunscreen use increased after transplantation (from a score of 1·4 to 2·1, P < 0·001). Sex, Fitzpatrick skin type, receiving advice to avoid sun from a healthcare provider, and pretransplantation sunscreen use were significantly associated with frequency of post-transplantation sunscreen use in multivariate models. Pretransplantation sun exposure, advice to avoid sun and pretransplantation sunscreen use were significantly associated with sun avoidance post-transplantation. Both patient features and clinician advice are associated with sun-protective behaviours after organ transplantation. These results will help physicians target expanded sun-protection counselling to those patients most in need of such intervention.

View details for DOI 10.1111/j.1365-2133.2012.11213.x

View details for PubMedID 22880814

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Low fat diet and skin cancer risk: the Women's Health Initiative Randomized Controlled Dietary Modification Trial.
Gamba CS, Stefanick M, Shikany J, Larson J, Linos E, Sims ST, Marshall JR, Van Horn L, Zeitouni N, Tang JY.
Cancer Epidemiol Biomarkers Prev. 2013  More 

              Abstract

Large cohort studies have reported no relationship between dietary fat and nonmelanoma skin cancer (NMSC), although a low-fat diet intervention reduced NMSC risk in a small clinical trial. In animal studies, skin tumor development has been reduced by low-fat diet. We evaluated the effect of a low-fat dietary pattern on NMSC and melanoma in the Women's Health Initiative Dietary Modification trial. Postmenopausal women aged 50 to 79 years (n = 48,835) were randomly assigned to the low-fat dietary pattern intervention (n = 19,541) or comparison group (n = 29,294). The intervention goals included decreasing fat intake to 20% or less of calories, increasing vegetable and fruit intake, and increasing grain intake. Self-reported incident NMSC (n = 4,907) and physician-adjudicated incident melanoma (n = 279) were ascertained every 6 months. Over 8.1 years of follow-up, the low-fat diet intervention did not affect overall incidence of NMSC [HR 0.98; 95% confidence interval (CI), 0.92-1.04] or melanoma (HR, 1.04; 95% CI, 0.82-1.32). In subgroup analyses of melanoma risk, baseline fat intake interacted significantly with group assignment (Pinteraction = 0.006). Among women with higher baseline fat intake, the dietary intervention significantly increased risk (HR, 1.48; 95% CI, 1.06-2.07), whereas, among women with lower baseline fat intake, the intervention tended to reduce melanoma risk (HR, 0.72; 95% CI, 0.50-1.02). In this large randomized trial, a low-fat dietary pattern did not affect overall incidence of NMSC or melanoma. A low-fat diet does not reduce incidence of NMSC, but an interaction between baseline fat intake and dietary intervention on melanoma risk warrants further investigation.

View details for DOI 10.1158/1055-9965.EPI-13-0341

View details for PubMedID 23697610

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New onset of keratoacanthomas after vismodegib treatment for locally advanced basal cell carcinomas: a report of 2 cases.
Aasi S, Silkiss  R, Tang JY, Wysong A, Liu A, Epstein E, Oro AE, Chang AL.
JAMA Dermatol. 2013; 149 (2); 242-3  More 

View details for DOI 10.1001/jamadermatol.2013.1798

View details for PubMedID 23426496

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Nonmelanoma skin cancer visits and procedure patterns in a nationally representative sample: national ambulatory medical care survey 1995-2007.
Wysong A, Linos E, Hernandez-Boussard T, Arron ST, Gladstone H, Tang JY. 
Dermatol Surg. 2013; 39 (4): 596-602  More 

              Abstract

The rising incidence of nonmelanoma skin cancer (NMSC) is well documented, but data are limited on the number of visits and treatment patterns of NMSC in the outpatient setting. To evaluate practice and treatment patterns of NMSC in the United States over the last decade and to characterize differences according to sex, age, race, insurance type, and physician specialty. Adults with an International Classification of Diseases, Ninth Revision, diagnosis of NMSC were included in this cross-sectional survey study of the National Ambulatory Medical Care Survey between 1995 and 2007. Primary outcomes included population-adjusted NMSC visit rates and odds ratios of receiving a procedure for NMSC using logistic regression. Rates of NMSC visits increased between 1995 and 2007. The number of visits was significantly higher in men, particularly those aged 65 and older. Fifty-nine percent of NMSC visits were associated with a procedure, and the individuals associated with that visit were more likely to be male, to be seen by a dermatologist, and to have private-pay insurance. Nonmelanoma skin cancer visit rates increased from 1995 to 2007 and were higher in men than women. Visits to a dermatologist are more likely to be associated with a procedure for NMSC, and there may be discrepancies in treatment patterns based on insurance type and sex.

View details for DOI 10.1111/dsu.12092

View details for PubMedID 23697610

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The use of aprepitant in brachioradial pruritus. 
Ally MS, Gamba CS, Peng DH, Tang JY.
JAMA Dermatol. 2013; 149 (5): 627-8  More 

View details for DOI 10.1001/jamadermatol.2013.170

View details for PubMedID 23677105

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Update on metastatic Basal cell carcinoma: a summary of published cases from 1981 through 2011.

Wysong A, Aasi SZ, Tang JY

JAMA Dermatol. 2013; 149 (5): 615-6  More 

View details for DOI 10.1001/jamadermatol.2013.3064

View details for PubMedID 23677097

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Does a history of eczema predict a future basal cell carcinoma? 
Gamba CA, Tang JY.
J Invest Dermatol. 2012; 132 (11): 2497-9  More 

              Abstract

Dyer et al. (this issue) assess the risk of new basal cell carcinoma (BCC) in the Veterans Affairs topical tretinoin chemoprevention trial, which included individuals with a history of at least two prior keratinocyte carcinomas. In addition to known risk factors for a future BCC, such as number of prior BCCs, a history of eczema and lower education levels were also associated with greater risk.

View details for DOI 10.1038/jid.2012.323

View details for PubMedID 23069907

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Is tanning bed exposure associated with aggressive basal cell carcinoma?
Gamba CA, Wysong A, Million L, Aasi S, Kim J, Tang JY.
J Clin Oncol. 2012; 30 (32): e333-6  More 

View details for DOI 10.1200/JCO.2012.42.1008

View details for PubMedID 23008324

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Nanoelectroablation therapy for murine basal cell carcinoma.
Nuccitelli R, Tran K, Athos B, Kreis M, Nuccitelli P, Chang KS, Epstein EH, Tang JY.
Biochem Biophys Res Commun. 2012; 424 (3): 446-50  More 

              Abstract

When skin tumors are exposed to non-thermal, low energy, nanosecond pulsed electric fields (nsPEF), apoptosis is initiated both in vitro and in vivo. This nanoelectroablation therapy has already been proven effective in treating subdermal murine allograft tumors. We wanted to determine if this therapy would be equally as effective in the treatment of autochthonous BCC tumors in Ptch1+/−K14-Cre-ER p53 fl/fl mice. These tumors are similar to human BCCs in histology [2;20] and in response to drug therapy [19]. We have treated 27 BCCs across 8 mice with either 300 pulses of 300 ns duration or 2700 pulses of 100 ns duration, all at 30 kV/cm and 5–7 pulses per second. Every nsPEF-treated BCC began to shrink within a day after treatment and their initial mean volume of 36 ± 5 (SEM) mm3 shrunk by 76 ± 3% over the ensuing two weeks. After four weeks, they were 99.8% ablated if the size of the treatment electrode matched the tumor size. If the tumor was larger than the 4 mm wide electrode, multiple treatments were needed for complete ablation. Treated tumors were harvested for histological analysis at various times after treatment and exhibited apoptosis markers. Specifically, pyknosis of nuclei was evident as soon as 2 days after nsPEF treatment, and DNA fragmentation as detected via TUNEL staining was also evident post treatment. Nanoelectroablation is effective in triggering apoptosis and remission of radiation-induced BCCs with a single 6 minute-long treatment of 2700 pulses.

View details for DOI 10.1016/j.bbrc.2012.06.129

View details for PubMedID 3415467

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Pachyonychia congenita patients with mutations in KRT6A have more extensive disease compared with patients who have mutations in KRT16.
Spaunhurst KM, Hogendorf AM, Smith FJ, Lingala B, Schwartz ME, Cywinska-Bernas A, Zeman KJ, Tang JY.
Br J Dermatol. 2012; 166 (4): 875-8  More 

              Abstract

Pachyonychia congenita (PC) is an autosomal dominant, very rare keratin disorder caused by mutations in any of at least four genes (KRT6A, KRT6B, KRT16 or KRT17), which can lead to hypertrophic nail dystrophy and palmoplantar keratoderma, among other manifestations. Classically, patients with mutations in KRT6A and KRT16 have been grouped to the PC-1 subtype (Jadassohn-Lewandowsky type) and KRT6B and KRT17 to PC-2 (Jackson-Lawler type). To describe clinical heterogeneity among patients with PC who have genetic mutations in KRT6A and KRT16. In 2004, the Pachyonychia Congenita Project established the International PC Research Registry (IPCRR) for patients with PC. All patients reporting here underwent genetic testing and responded to a standardized, validated survey about their PC symptoms. We report results from 89 patients with KRT6A mutations and 68 patients with KRT16 mutations. Patients with PC who have KRT6A and KRT16 mutations display distinct phenotypic differences. Patients with PC-K6a experience earlier onset, more extensive nail disease and more substantial disease outside palms and soles, as they reported a higher prevalence of oral leucokeratosis (P < 0·001), cysts (P < 0·001) and follicular hyperkeratosis (P < 0·001) compared with their PC-K16 counterparts. Phenotypic differences between patients with KRT6A and KRT16 mutations support adoption of a new classification system based on the mutant gene (PC-6a, PC-16) rather than the PC-1 nomenclature.

View details for DOI 10.1111/j.1365-2133.2011.10745.x

View details for PubMedID 22098151

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Reliability and prevalence of digital image skin types in the United States: results from National Health and Nutrition Examination Survey 2003-2004. 
Keiser E, Linos E, Kanzler M, Lee W, Sainani KL, Tang JY.
J Am Acad Dermatol. 2012; 66 (1): 163-5  More             

View details for DOI 10.1016/j.jaad.2011.02.044

View details for PubMedID 22177642

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Sun protective behaviors and vitamin D levels in the US population: NHANES 2003-2006.
Linos E, Keiser E, Kanzler M, Sainani KL, Lee W, Vittinghoff E, Chren MM, Tang JY.
Cancer Causes Control. 2012; 23 (1): 133-40  More 

              Abstract

Sun protection is recommended for skin cancer prevention, yet little is known about the role of sun protection on vitamin D levels. Our aim was to investigate the relationship between different types of sun protective behaviors and serum 25(OH)D levels in the general US population. Cross-sectional, nationally representative survey of 5,920 adults aged 18-60 years in the US National Health and Nutrition Examination Survey 2003-2006. We analyzed questionnaire responses on sun protective behaviors: staying in the shade, wearing long sleeves, wearing a hat, using sunscreen and SPF level. Analyses were adjusted for multiple confounders of 25(OH)D levels and stratified by race. Our primary outcome measures were serum 25(OH)D levels (ng/ml) measured by radioimmunoassay and vitamin D deficiency, defined as 25(OH)D levels <20 ng/ml. Staying in the shade and wearing long sleeves were significantly associated with lower 25(OH)D levels. Subjects who reported frequent use of shade on a sunny day had -3.5 ng/ml (p (trend) < 0.001) lower 25(OH)D levels compared to subjects who reported rare use. Subjects who reported frequent use of long sleeves had -2.2 ng/ml (p (trend) = 0.001) lower 25(OH)D levels. These associations were strongest for whites, and did not reach statistical significance among Hispanics or blacks. White participants who reported frequently staying in the shade or wearing long sleeves had double the odds of vitamin D deficiency compared with those who rarely did so. Neither wearing a hat nor using sunscreen was associated with low 25(OH)D levels or vitamin D deficiency. White individuals who protect themselves from the sun by seeking shade or wearing long sleeves may have lower 25(OH)D levels and be at risk for vitamin D deficiency. Frequent sunscreen use does not appear to be linked to vitamin D deficiency in this population.

View details for DOI 10.1007/s10552-011-9862-0

View details for PubMedID 22045154

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Sunscreen use in NCAA collegiate athletes: identifying targets for intervention and barriers to use.
Wysong A, Gladstone H, Kim D, Lingala B, Copeland J, Tang JY. 
Prev Med. 2012; 55 (5): 493-6  More 

              Abstract

Ultraviolet radiation is a known risk factor for skin cancer and photoaging. Athletes are at high-risk with frequent sun exposure during peak hours of ultraviolet radiation. The aim of this study was to identify attitudes, personal characteristics, and barriers associated with sunscreen use among a high-risk athlete population. A cross-sectional survey study conducted in 290 collegiate athletes from April 2010 to June 2011 at Duke and Stanford Universities. The average athlete spent 4h per day and 10 months per year training outdoors. While 96% agreed that sunscreen helps prevent skin cancer, over 50% never used sunscreen and 75% used sunscreen 3 or fewer days/week. Having a coach or athletic administrator discuss photoprotection was significantly associated with sunscreen use. Predictors of sunscreen use were female gender, sunburns in the last year, belief at risk for skin cancer, knowing someone with skin cancer, and being worried about wrinkles, sun burns, or skin cancer. Continued identification of characteristics and barriers to sunscreen use can lead to targeted interventions and education in this high-risk group of collegiate athletes with early and elevated total lifetime ultraviolet exposure.

View details for DOI 10.1016/j.ypmed.2012.08.020

View details for PubMedID 22975268

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The evolving conception and management challenges of malignant fibrous histiocytoma. 
Hollmig ST, Kirkland EB, Henderson MT, Tang JY, Gladstone HB.
Dermatol Surg. 2012; 38 (12): 1922-9  More 

              Abstract

Malignant fibrous histiocytoma (MFH) is a rare and aggressive tumor. Mohs micrographic surgery (MMS) has been reported as an effective treatment, although most cases were published before advances in cytopathologic techniques led to reclassification of many tumors. To evaluate a contemporary cohort of individuals with MFH and analyze management practices. We reviewed all cases of MFH diagnosed at our institution from January 1995 to December 2010, evaluating 839 records to identify 36 patients undergoing management of tumors of the head and neck. Seventeen of the total 36 patients (47%; mean age 67) experienced tumor recurrence, and 10 (28%) developed metastases. Seven of nine patients initially treated with MMS (78%), and 10 of 24 (42%) treated with WLE experienced recurrence (p = .06). Patients treated with MMS had smaller tissue defects after surgery. The mean contemporary recurrence rate of MFH treated with MMS is significantly higher (58.8%) than the cumulative recurrence rate reported before 2000 (7.4%) (p < .001). Our study is consistent with reports of MFH as an aggressive neoplasm and describes the largest population treated with MMS in 3 decades. The changing conception of MFH, along with a propensity for in-transit metastases, may explain higher contemporary recurrence rates. 

View details for DOI 10.1111/j.1524-4725.2012.02538.x

View details for PubMedID 22882717

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Vitamin D in cutaneous carcinogenesis: Part I. 
Tang JY, Fu T, Lau C, Oh DH, Bikle DD, Asgari MM.
J Am Acad Dermatol. 2012; 67 (5): 803.e1-12, quiz 815-6  More 

              Abstract

Skin cancer is the most common cancer in the United States. Exposure to ultraviolet radiation is a known risk factor for skin cancer but is also the principal means by which the body obtains vitamin D. Several studies have suggested that vitamin D plays a protective role in a variety of internal malignancies. With regard to skin cancer, epidemiologic and laboratory studies suggest that vitamin D and its metabolites may have a similar protective effect. These noncalcemic actions of vitamin D have called into question whether the current recommended intake of vitamin D is too low for optimal health and cancer prevention. Part I will review the role of vitamin D in the epidermis; part II will review the role of vitamin D in keratinocyte-derived tumors to help frame the discussion on the possible role of vitamin D in the prevention of skin cancer.

View details for DOI 10.1016/j.jaad.2012.05.044

View details for PubMedID 23062903

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Vitamin D in cutaneous carcinogenesis: Part II. 
Tang JY, Fu T, Lau C, Oh DH, Bikle DD, Asgari MM.
J Am Acad Dermatol. 2012; 67 (5): 817.e1-11, quiz 827-8  More 

              Abstract

The role of vitamin D in health maintenance and disease prevention in fields ranging from bone metabolism to cancer is currently under intensive investigation. A number of epidemiologic studies have suggested that vitamin D may have a protective effect on cancer risk and cancer-associated mortality. With regard to skin cancer, epidemiologic and laboratory studies suggest that vitamin D and its metabolites may have a similar risk reducing effect. Potential mechanisms of action include inhibition of the hedgehog signaling pathway and upregulation of nucleotide excision repair enzymes. The key factor complicating the association between vitamin D and skin cancer is ultraviolet B radiation. The same spectrum of ultraviolet B radiation that catalyzes the production of vitamin D in the skin also causes DNA damage that can lead to epidermal malignancies. Part II of this continuing medical education article will summarize the literature on vitamin D and skin cancer to identify evidence-based optimal serum levels of vitamin D and to recommend ways of achieving those levels while minimizing the risk of skin cancer.

View details for DOI 10.1016/j.jaad.2012.07.022

View details for PubMedID 23062904

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Correlates of low bone mass in children with generalized forms of epidermolysis bullosa.
Bruckner AL, Bedocs LA, Keiser E, Tang JY, Doernbrack C, Arbuckle HA, Berman S, Kent K, Bachrach LK.
J Am Dermatol. 2011; 65 (5): 1001-9  More 

              Abstract

Epidermolysis bullosa (EB) is a family of rare, heterogeneous, genetic disorders characterized by fragility of the skin and mucous membranes. Reduced bone mass and fractures have been recognized as complications of generalized forms of EB. We sought to describe the range and to estimate the prevalence of low bone mass in children with generalized EB, and to identify correlates of low bone mass in this population. This was a prospective, observational study of 24 patients with generalized EB. Each patient completed a history, physical examination, laboratory studies, bone age, and x-rays of the lumbar spine. Those aged 6 years and older underwent dual energy x-ray absorptiometry scans of the lumbar spine. Primary outcomes were areal bone mineral density (aBMD) based on chronologic age, bone age, and adjusted for height Z-score. Descriptive statistics were used to summarize results, and linear regression was used to determine factors associated with low aBMD. Mean lumbar spine aBMD Z-scores ± SD were: -2.6 ± 1.4 for chronologic age, -1.7 ± 1.3 for bone age, and -1.0 ± 1.2 after adjusting for height Z-score. aBMD Z-scores were less than or equal to -2 in 64% for chronologic age, 50% for bone age, and 28% after adjusting for height Z-score. aBMD correlated with height Z-score, weight Z-score, extensive blistering, immobility, albumin, hemoglobin, iron, erythrocyte sedimentation rate, and c-reactive protein values. Small sample size was a limitation. Children with severe, generalized recessive dystrophic EB have low aBMD for age. Deficits in aBMD were reduced after adjusting for delayed skeletal maturation and small body size.

View details for DOI 10.1016/j.jaad.2010.08.028

View details for PubMedID 21550693

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Elucidating the role of molecular signaling pathways in the tumorigenesis of basal cell carcinoma.
Tang JY
Semin Cutan Med Surg. 2011; 30 (4 Suppl): S6-9  More 

              Abstract

The Hedgehog signaling pathway has been identified as fundamentally important to normal embryonic development in living organisms ranging from fruit flies to mammals. Postdevelopmentally, it remains active in hair and skin cells. Abnormal activation of components of the Hedgehog pathway--specifically, resulting from mutations in the Patched 1 gene--is associated with the development of basal cell carcinoma, as well as several other cancers, including medulloblastoma. Patched 1 gene mutation has also been identified as the underlying mechanism in most cases of Gorlin syndrome (also known as basal cell nevus syndrome or nevoid basal cell carcinoma syndrome). Research that resulted in the current understanding of the Hedgehog signaling pathway, in turn, led to multiple lines of investigation to discover mechanisms for halting abnormal signaling, in the hope that agents could be developed that could beneficially stop this pathway. To date, several agents have been developed-and some are in clinical trials-that hold promise for improved nonsurgical treatments for patients with Gorlin syndrome and those with locally advanced/metastatic BCCs.

View details for DOI 10.1016/j.sder.2011.11.001

View details for PubMedID 22177103

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Emerging treatments and signaling pathway inhibitors.
Tang JY, Marghoob AA.
Semin Cutan Med Surg. 2011; 30 (4 Suppl): S14-8  More 

              Abstract

A number of therapies that target components of the Hedgehog signaling pathway currently are in clinical trials. The specific molecules that seem most promising in basal cell carcinoma and a number of other cancers are those that target the Smoothened transmembrane protein. The pivotal phase II trials have been completed on the Smoothened inhibitor known as GDC-0449; five other agents (BMS-833923, LDE225, LEQ506, IPI926, and TAK-441) have also shown promise in animal studies and early clinical trials and have shown some efficacy in a variety of cancers that are affected by the Hedgehog signaling pathway.

View details for DOI 10.1016/j.sder.2011.11.002

View details for PubMedID 22177102

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Genotype-phenotype correlations among pachyonychia congenita patients with K16 mutations.
Fu T, Leachman SA, Wilson NJ, Smith FJ, Schwartz ME, Tang JY.
J Invest Dermatol. 2011; 131 (5): 1025-8  More 

              Abstract

Pachyonychia congenita (PC) is a rare, autosomal dominant keratin disorder caused by mutations in four genes (KRT6A, KRT6B, KRT16, or KRT17). The International PC Research Registry is a database with information on patients' symptoms as well as genotypes. We sought to describe the heterogeneity of clinical symptoms and to investigate possible genotype-phenotype correlations in patients with two types of K16 mutations, p.Asn125 and p.Arg127, causing the PC-16 subtype of PC. We found that clinical symptoms depended on the type of amino-acid substitution. Patients with p.Asn125Asp and p.Arg127Pro mutations exhibited more severe disease than patients carrying p.Asn125Ser and p.Arg127Cys mutations in terms of age of onset of symptoms, extent of nail involvement, and impact on daily quality of life. We speculate that amino-acid substitutions causing larger, more disruptive changes to the K16 protein structure, such as a change in amino-acid charge in the p.Asn125Asp mutation or a bulky proline substitution in the p.Arg127Pro mutation, may also lead to more severe disease phenotypes. The variation in phenotypes seen with different substitutions at the same mutation site suggests a genotype-phenotype correlation. Knowledge of the exact gene defect is likely to assist in predicting disease prognosis and clinical management.

View details for DOI 10.1038/jid.2010.373

View details for PubMedID 21160496

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Hat, shade, long sleeves, or sunscreen? Rethinking US sun protection messages based on their relative effectiveness. 

Linos E, Keiser E, Fu T, Colditz G, Chen S, Tang JY.

Cancer Causes Control. 2011; 22 (7): 1067-71  More 

              Abstract

Sun protection messages in the United States emphasize sunscreen use, although its efficacy in skin cancer prevention remains controversial. We used data from NHANES 2003-2006, restricted to adult whites (n = 3,052) to evaluate how Americans protect themselves from the sun. Participants completed questionnaires on the frequency with which they used sunscreen, wore a hat, long sleeves, or stayed in the shade, in addition to the number of sunburns in the past year. Although using sunscreen is the most common sun protective behavior (30%), frequent sunscreen use was not associated with fewer sunburns. However, the odds of multiple sunburns were significantly lower in individuals who frequently avoided the sun by seeking shade (OR = 0.70, p < 0.001) or wearing long sleeves (OR = 0.73, p = 0.01). Our findings suggest that shade and protective clothing may be more effective than sunscreen, as typically used by Americans.

View details for DOI 10.1007/s10552-011-9780-1

View details for PubMedID 21637987

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Menopausal hormone therapy and risks of melanoma and nonmelanoma skin cancers: women's health initiative randomized trials.

Tang JY, Spaunhurst KM, Chlebowski RT, Wactawski-Wende J, Keiser E, Thomas F, Anderson ML, Zeitouni NC, Larson JC, Stefanick ML.

J Natl Cancer Inst. 2011; 103 (19): 1469-75  More 

              Abstract

Case-control studies have reported that exogenous estrogen use is associated with increased risk of skin cancer. The effects of menopausal hormone therapy on incidence of nonmelanoma skin cancer and melanoma were evaluated in post hoc analyses of the Women's Health Initiative randomized placebo-controlled hormone therapy trials of combined estrogen plus progestin (E + P) and estrogen only (E-alone). Postmenopausal women aged 50-79 years were randomly assigned to conjugated equine estrogen (0.625 mg/d) plus medroxyprogesterone acetate (2.5 mg/d) or placebo in the E + P trial if they had an intact uterus (N = 16,608) or to conjugated equine estrogen alone or placebo in the E-alone trial if they had a hysterectomy (N = 10,739); the mean follow-up was 5.6 and 7.1 years, respectively. Incident nonmelanoma skin cancers (n = 980 [E + P trial]; n = 820 [E-alone trial]) and melanomas (n = 57 [E + P trial]; n =38 [E-alone trial]) were ascertained by self-report. Incident cases of cutaneous malignant melanoma were confirmed by physician review of medical records. Incidences of nonmelanoma skin cancer and melanoma were compared between the two randomization groups within each trial using hazard ratios (HRs), with corresponding 95% confidence intervals (CIs) and Wald statistic P values from Cox proportional hazards models. All statistical tests were two-sided. Rates of incident nonmelanoma skin cancer and melanoma were similar between the active hormone (combined analysis of E + P and E-alone) and placebo groups (nonmelanoma skin cancer: HR = 0.98, 95% CI = 0.89 to 1.07; melanoma: HR = 0.92, 95% CI = 0.61 to 1.37). Results were similar for the E + P and E-alone trials when analyzed individually. Menopausal hormone therapy did not affect overall incidence of nonmelanoma skin cancer or melanoma. These findings do not support a role of menopausal estrogen, with or without progestin, in the development of skin cancer in postmenopausal women.

View details for DOI 10.1093/jnci/djr333

View details for PubMedID 21878677

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Subcataneous nodules in an elderly patient. Necrobiotic xanthogranuloma.

Fu T, Zwerner J, Kim J, Tang J.

Arch Dermatol. 2011; 147 (10): 1215-20  More 

View details for DOI 10.1001/archdermatol.2011.285-a

View details for PubMedID 22006142

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Targeting superficial or nodular Basal cell carcinoma with topically formulated small molecule inhibitor of smoothened. 

Tang T, Tang JY, Li D, Reich M, Callahan CA, Fu L, Yauch RL, Wang F, Kotkow K, Chang KS, Shpall E, Wu A, Rubin LL, Marsters JC, Epstein EH, Caro I, de Sauvage FJ.

Clin Cancer Res. 2011; 17 (10): 3378-87  More 

              Abstract

Inappropriate activation of the Hedgehog (Hh) signaling pathway in skin is critical for the development of basal cell carcinomas (BCC). We have investigated the anti-BCC efficacy of topically-applied CUR61414, an inhibitor of the Hh signal transduction molecule Smoothened. In preclinical studies, we used a depilatory model to evaluate the ability of topical formulations of CUR61414 to repress Hh responsive cells found at the base of hair follicles in normal skin. We also tested the in vivo effects of topical CUR61414 on murine BCCs developed in Ptch1 (+/-) K14-CreER2 p53 fl/fl mice. In a phase I clinical study, we evaluated the safety, tolerability, and efficacy of a multidose regimen of CUR61414 (0.09%, 0.35%, 1.1%, and 3.1%) applied topically to human superficial or nodular BCCs for up to 28 days. In mice, topical CUR61414 significantly inhibited skin Hh signaling, blocked the induction of hair follicle anagen, and shrank existing BCCs. However, we observed no clinical activity of this formulation in human superficial or nodular BCCs in a phase I clinical study. Our data highlight some of the challenges of translating preclinical experience into successful human results for a topical anticancer agent.

View details for DOI 10.1158/1078-0432.CCR-10-3370

View details for PubMedID 21558397

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Vitamin D3 inhibits hedgehog signaling and proliferation in murine Basal cell carcinomas. 

Tang JY, Xiao TZ, Oda Y, Chang KS, Shpall E, Wu A, So PL, Hebert J, Bikle D, Epstein EH.

Cancer Prev Res (Phila). 2011; 4 (5): 744-51  More 

              Abstract

Constitutive Hedgehog (HH) signaling underlies several human tumors, including basal cell carcinoma (BCC). Recently, Bijlsma and colleagues reported a new biologic function for vitamin D3 in suppressing HH signaling in an in vitro model system. On the basis of that work, we have assessed effects of vitamin D3 on HH signaling and proliferation of murine BCCs in vitro and in vivo. We find that indeed in BCC cells, vitamin D3 blocks both proliferation and HH signaling as assessed by mRNA expression of the HH target gene Gli1. These effects of vitamin D3 on Gli1 expression and on BCC cell proliferation are comparable to the effects of cyclopamine, a known inhibitor of the HH pathway. These results are specific for vitamin D3, because the precursor 7-dehydrocholesterol and the downstream products 25-hydroxy vitamin D3 [25(OH)D] and 1,25-dihydroxy vitamin D3 [1,25(OH)(2)D] are considerably less effective in reducing either Gli1 mRNA or cellular proliferation. Moreover, these effects seem to be independent of the vitamin D receptor (VDR) because short hairpin RNA knockdown of VDR does not abrogate the anti-HH effects of D3 despite reducing expression of the VDR target gene 24-hydroxylase. Finally, topical vitamin D3 treatment of existing murine BCC tumors significantly decreases Gli1 and Ki67 staining. Thus, topical vitamin D3 acting via its HH inhibiting effect may hold promise as an effective anti-BCC agent.

View details for DOI 10.1158/1940-6207.CAPR-10-0285

View details for PubMedID 21436386

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Association of facial skin aging and vitamin D levels in middle-aged white women.

Chang AL, Fu T, Amir O, Tang JY.

Cancer Causes Control. 2010; 21 (12): 2315-6  More 

              Abstract

To investigate the relationship between UV-induced skin photodamage and 25(OH) vitamin D levels, we performed a cross-sectional study in 45 female subjects aged >40. Menopausal status, smoking status, skin cancer history, oral supplement use, and season of blood draw were recorded and serum 25(OH)D measured. A single-blinded, dermatologist evaluated standardized digital facial images for overall photodamage, erythema/telangiectasias, hyperpigmentation, number of lentigines, and wrinkling. Adjusting for age and season of blood collection, women with lower photodamage scores were associated with a 5-fold increased odds of being vitamin D insufficient (OR 5.0, 95% CI: 1.1, 23). Low scores for specific photodamage parameters including erythema/telangiectasias, hyperpigmentation, and wrinkling were also significantly associated with vitamin D insufficiency. Our results suggest an association between skin aging and 25(OH)D levels.

View details for DOI 10.1007/s10552-010-9646-y

View details for PubMedID 20882333

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Association of prediagnostic serum vitamin D levels with the development of basal cell carcinoma.

Asgari MM, Tang J, Warton ME, Chren MM, Quesenberry CP, Bikle D, Horst RL, Orentreich N, Vogelman JH, Friedman GD:

J Invest Dermatol. 2010; 130 (5): 1438-43  More 

              Abstract

We investigated the association between serum 25-hydroxyvitamin D (25(OH)D) levels and basal cell carcinoma (BCC) risk in a nested case-control study at Kaiser Permanente Northern California (KPNC). A total of 220 case patients with BCC diagnosed after serum collection were matched to 220 control subjects. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) using conditional logistic regression. Fully adjusted models included body mass index (BMI), smoking, education, sun-exposure variables, X-ray exposure, and personal history of cancer. For each measure of serum 25(OH)D (continuous, clinically relevant tertiles, quintiles), we found an increased risk of BCC in unadjusted models (OR=1.03, 95% CI 1.00-1.05, P<0.05; OR=3.98, 95% CI: 1.31-12.31, deficient vs. sufficient, test for trend P-value <0.01; OR=2.32, 95% CI: 1.20-4.50, 1st vs. 5th quintile, test for trend P-value 0.03). In fully adjusted models, the values attenuated slightly (OR=1.02, 95% CI 1.00-1.05, P<0.05; OR=3.61, 95% CI: 1.00-13.10, deficient vs. sufficient, t-trend P=0.03; OR=2.09 1st vs. 5th quintile, 95% CI: 0.95-4.58, t-trend P=0.11). Our findings suggest that higher prediagnostic serum 25(OH)D levels may be associated with increased risk of subsequent BCC. Further studies to evaluate the effect of sun exposure on BCC and serum 25(OH)D levels may be warranted.

View details for DOI 10.1038/jid.2009.402

View details for PubMedID 20043012

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Basal cell carcinoma chemoprevention with nonsteroidal anti-inflammatory drugs in genetically predisposed PTCH1+/- humans and mice.

Tang JY, Aszterbaum M, Athar M, Barsanti F, Cappola C, Estevez N, Hebert J, Hwang J, Khaimskiy Y, Kim A, Lu Y, So PL, Tang X, Kohn MA, McCulloch CE, Kopelovich L, Bickers DR, Epstein EH. 

Cancer Prev Res (Phila). 2010; 3 (1): 24-34  More 

              Abstract

In vitro and epidemiologic studies favor the efficacy of nonsteroidal anti-inflammatory drugs (NSAID) in preventing skin squamous photocarcinogenesis, but there has been relatively little study of their efficacy in preventing the more common skin basal cell carcinoma (BCC) carcinogenesis. We first compared the relative anti-BCC effects of genetic deletion and NSAID pharmacologic inhibition of cyclooxygenase (COX) enzymes in the skin of Ptch1(+/-) mice. We then assessed the effects of celecoxib on the development of BCCs in a 3-year, double-blinded, randomized clinical trial in 60 (PTCH1(+/-)) patients with the basal cell nevus syndrome. In Ptch1(+/-) mice, genetic deletion of COX1 or COX2 robustly decreased (75%; P < 0.05) microscopic BCC tumor burden, but pharmacologic inhibition with celecoxib reduced microscopic BCCs less efficaciously (35%; P < 0.05). In the human trial, we detected a trend for oral celecoxib reducing BCC burden in all subjects (P = 0.069). Considering only the 60% of patients with less severe disease (<15 BCCs at study entry), celecoxib significantly reduced BCC number and burden: subjects receiving placebo had a 50% increase in BCC burden per year, whereas subjects in the celecoxib group had a 20% increase (P(difference) = 0.024). Oral celecoxib treatment inhibited BCC carcinogenesis in PTCH1(+/-) mice and had a significant anti-BCC effect in humans with less severe disease.

View details for DOI 10.1158/1940-6207.CAPR-09-0200

View details for PubMedID 20051370

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High prevalence of vitamin D deficiency in patients with basal cell nevus syndrome.

Tang JY, Wu A, Linos E, Parimi N, Lee W, Aszterbaum M, Asgari MM, Bickers DR, Epstein EH.

Arch Dermatol. 2010; 146 (10): 1105-10  More 

              Abstract

To evaluate vitamin D status in patients with basal cell nevus syndrome (BCNS) who practice photoprotection because of their genetic predisposition to skin cancer and to determine risk factors for deficiency. 

Retrospective cohort study.

Academic medical centers.

Forty-one ambulatory patients with BCNS who participated in a 2-year chemoprevention clinical trial. Population-based controls (n = 360) were selected and matched by age, sex, Fitzpatrick skin type, and season/geography

Levels of 25-hydroxyvitamin D (25[OH]D) and vitamin D deficiency (defined as a 25[OH]D level of ≤20 ng/mL). 

Twenty-three patients with BCNS (56%) were vitamin D deficient. Patients with BCNS had mean 25(OH)D levels below those of the general population (-3 ng/mL; P = .02) and were 3 times more likely to be vitamin D deficient (56% vs 18%; P < .001). Levels of 25(OH)D were lower in patients who were overweight (-3.0 ng/mL; P = .04) and who had blood collected in the winter compared with the summer (-7.1 ng/mL; P < .001).

Patients with BCNS may be at increased risk for vitamin D deficiency, depending on their adherence to photoprotection practices.

View details for DOI 10.1001/archdermatol.2010.247

View details for PubMedID 20956641

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Inverse association between serum 25(OH) vitamin D levels and non-melanoma skin cancer in elderly men.

Tang JY, Parimi N, Wu A, Boscardin WJ, Shikany JM, Chren MM, Cummings SR, Epstein EH, Bauer DC.

Cancer Causes Control. 2010; 21 (3): 387-91  More 

              Abstract

To determine the relationship between 25(OH) vitamin D levels and non-melanoma skin cancer (NMSC), we performed a nested case-control study in ambulatory, elderly men enrolled in the Osteoporotic Fractures in Men (MrOS) Study. Health habit and medical history, including self-reported history of NMSC were recorded and 25(OH)D levels were measured on serum collected at baseline from a random sample of Caucasian MrOS subjects. Mean age (73 +/- 5), BMI, daily vitamin D and calcium intake were similar in the men with (n = 178) and without NMSC (n = 930), but higher levels of 25(OH)D were associated with a decreased risk of having a history of NMSC (P(trend) = 0.04). Men in the highest quintile of 25(OH)D (>30 ng/mL) had 47% lower odds of NMSC (95% CI: 0.30-0.93, p = 0.026) compared to those in the lowest quintile. Our results suggest that a diagnosis of NMSC is not a surrogate for adequate 25(OH)D levels or increased UV exposure, and high 25(OH)D levels may be associated with a reduced risk of NMSC.

View details for DOI 10.1007/s10552-009-9470-4

View details for PubMedID 19921445

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Itraconazole, a commonly used antifungal that inhibits Hedgehog pathway activity and cancer growth.

Kim J, Tang JY, Gong R, Kim J, Lee JJ, Clemons KV, Chong CR, Chang KS, Fereshteh M, Gardner D, Reya T, Liu JO, Epstein EH, Stevens DA, Beachy PA. 

Cancer Cell. 2010; 17 (4): 388-99  More 

              Abstract

In a screen of drugs previously tested in humans we identified itraconazole, a systemic antifungal, as a potent antagonist of the Hedgehog (Hh) signaling pathway that acts by a mechanism distinct from its inhibitory effect on fungal sterol biosynthesis. Systemically administered itraconazole, like other Hh pathway antagonists, can suppress Hh pathway activity and the growth of medulloblastoma in a mouse allograft model and does so at serum levels comparable to those in patients undergoing antifungal therapy. Mechanistically, itraconazole appears to act on the essential Hh pathway component Smoothened (SMO) by a mechanism distinct from that of cyclopamine and other known SMO antagonists, and prevents the ciliary accumulation of SMO normally caused by Hh stimulation.

View details for DOI 10.1016/j.ccr.2010.02.027

View details for PubMedID 20385363

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Medical Management of Advanced or Metastatic Basal Cell Carcinomas

Jean Y Tang, Ervin H. Epstein.

AccessMedicine from McGraw-Hill. 2010  More 

              Abstract

Improved treatments of basal cell carcinoma (BCC) represent one of the triumphs of modern Dermatology in that rates of cure have increased from the approximately 95% best of past generations' simple excision with appropriate margins or ionizing radiation to 98-99% with microscopically controlled dissection—Mohs surgery. Accompanying this have been improved cosmetic results as surgical skills have improved. Nonetheless there exists significant room for improvement. Such "room" can be considered under several categories—herein prevention and medical treatment, as opposed to physical ablation.

View details for full text

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Novel investigational drugs for basal cell carcinoma.

So PL, Tang JY, Epstein EH.

Expert Opin Investig Drugs. 2010; 19 (9): 1099-112  More 

              Abstract

Importance of the field: In the United States, the annual incidence of basal cell carcinoma (BCC) is close to 1 million. Ultraviolet radiation exposure is the main risk factor; however, the availability of ever more potent sunscreens and education have not prevented the rise in BCC incidence. Therefore, concerted effects to identify novel preventive and therapeutic strategies are necessary.

Areas covered in this review: This article summarizes our current understanding of the etiology and molecular mechanisms of BCC tumorigenesis and discusses the preclinical and clinical studies to identify agents with anti-BCC efficacy.

What the reader will gain: The discovery that hyperactive Hh pathway signaling causes several cancers, including BCC, has spawned the development of many pharmacologic inhibitors of Hh signaling. Early clinical testing of the most advanced, GDC-0449, demonstrated impressive efficacy in patients with advanced BCC. Other promising anti-BCC chemopreventive strategies include drugs that are already FDA-approved for treating other diseases.

Take home message: Preclinical and clinical trials with pre-existing FDA-approved drugs suggest novel uses for BCC chemoprevention and treatment. Also, new chemical entities that inhibit the Hh pathway show promise, and in combination with other drugs may provide a nonsurgical cure for this most common cancer.

View details for DOI 10.1517/13543784.2010.504714

View details for PubMedID 20662553

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Statin use and risk of basal cell carcinoma.

Asgari MM, Tang J, Epstein EH, Chren MM, Warton EM, Quesenberry CP, Go AS, Friedman GD.

J Am Acad Dermatol. 2009; 61 (1): 66-72  More 

              Abstract

Objective: We examined the association between statin use and basal cell carcinoma (BCC) risk.

Methods: We identified all members of a large integrated health care delivery system with a diagnosis of a histologically proven BCC in 1997. Subsequent BCCs were identified through 2006 from health plan electronic pathology records. Longitudinal exposure to statins and other lipid-lowering agents was determined from automated pharmacy records. We used extended Cox regression to examine the independent association between receipt of statin therapy (ever vs never, cumulative duration) and risk of subsequent BCC. To minimize confounding by indication, we conducted sensitivity analyses in the subset of individuals considered eligible for lipid-lowering therapy based on national guidelines.

Results: Among 12,123 members given a diagnosis of BCC who had no prior statin exposure, 6381 developed a subsequent BCC during follow-up. Neither "ever use of statins" (adjusted hazard ratio 1.02, 95% confidence interval: 0.92-1.12) or cumulative duration of statin (adjusted hazard ratio 1.02/year, 95% confidence interval: 0.99-1.11) was associated with subsequent BCC after adjustment for age, sex, and health care use. Risk estimates did not change appreciably when the analysis was limited to the subset of individuals who met eligibility criteria for initiating statin therapy. There was also no significant association between use of non-statin antilipemics and subsequent BCC (adjusted hazard ratio 1.10, 95% confidence interval: 0.76-1.58).

Limitations: No information was available for BCC risk factors, such as sun sensitivity and sun exposure.

Conclusions: Among a large cohort of individuals with BCC, statin therapy was not significantly associated with risk of subsequent BCC.

View details for DOI 10.1016/j.jaad.2009.02.011

View details for PubMedID 19464071

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Novel Hedgehog pathway targets against basal cell carcinoma. 

Tang JY, So PL, Epstein EH.

Toxicol Appl Pharmacol. 2007; 224 (3): 257-64  More 

              Abstract

The Hedgehog signaling pathway plays a key role in directing growth and patterning during embryonic development and is required in vertebrates for the normal development of many structures, including the neural tube, axial skeleton, skin, and hair. Aberrant activation of the Hedgehog (Hh) pathway in adult tissue is associated with the development of basal cell carcinoma (BCC), medulloblastoma, and a subset of pancreatic, gastro-intestinal, and other cancers. This review will provide an overview of what is known about the mechanisms by which activation of Hedgehog signaling leads to the development of BCCs and will review two recent papers suggesting that agents that modulate sterol levels might influence the Hh pathway. Thus, sterols may be a new therapeutic target for the treatment of BCCs, and readily available agents such as statins (HMG-CoA reductase inhibitors) or vitamin D might be helpful in reducing BCC incidence.

View details for DOI 10.1016/j.taap.2006.12.011

View details for PubMedID 2719777

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Xeroderma pigmentosum group C in an isolated region of Guatemala. 

Cleaver JE, Feeney L, Tang JY, Tuttle P.

J Invest Dermatol. 2007; 127 (2): 493-6  More 

View details for DOI 10.1038/sj.jid.5700555

View details for PubMedID 3031115

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Toxicity from radiation therapy associated with abnormal transcriptional responses to DNA damage. 

Rieger KE, Hong WJ, Tusher VG, Tang J, Tibshirani R, Chu G. 

Proc Natl Acad Sci U S A. 2004; 101 (17): 6635-40  More 

              Abstract

Toxicity from radiation therapy is a grave problem for cancer patients. We hypothesized that some cases of toxicity are associated with abnormal transcriptional responses to radiation. We used microarrays to measure responses to ionizing and UV radiation in lymphoblastoid cells derived from 14 patients with acute radiation toxicity. The analysis used heterogeneity-associated transformation of the data to account for a clinical outcome arising from more than one underlying cause. To compute the risk of toxicity for each patient, we applied nearest shrunken centroids, a method that identifies and cross-validates predictive genes. Transcriptional responses in 24 genes predicted radiation toxicity in 9 of 14 patients with no false positives among 43 controls (P = 2.2 × 10-7). The responses of these nine patients displayed significant heterogeneity. Of the five patients with toxicity and normal responses, two were treated with protocols that proved to be highly toxic. These results may enable physicians to predict toxicity and tailor treatment for individual patients.

View details for DOI 10.1073/pnas.0307761101

View details for PubMedID 404097

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Interaction between UV-damaged DNA binding activity proteins and the c-Abl tyrosine kinase. 

Cong F, Tang J, Hwang BJ, Vuong BQ, Chu G, Goff SP.

J Biol Chem, 2002; 277 (38): 34870-8  More 

              Abstract

The c-Abl tyrosine kinase is activated by some forms of DNA damage, including ionizing radiation, but not UV radiation. The functions of this activation in the damage response pathways remain obscure. To identify potential targets of c-Abl kinase, we utilized the yeast two-hybrid system to screen a murine cDNA library. One c-Abl binding protein of particular interest was the large subunit (DDB1) of the heterodimeric complex with UV-damaged DNA binding activity (UV-DDB). This complex binds with high specificity to DNA damaged by UV, is absent in a subset of xeroderma pigmentosum group E cells, and is required for global genomic repair of UV-induced damage. The association of c-Abl with DDB1 required the kinase domain of c-Abl and preserved the interaction between DDB1 and the small subunit (DDB2) of the UV-DDB complex. Significantly, overexpression of c-Abl increased tyrosine phosphorylation of DDB2 and suppressed UV-DDB activity. Conversely, a dominant negative, kinase-deficient allele of c-Abl decreased tyrosine phosphorylation of DDB2 and dramatically stimulated UV-DDB activity. These results suggest that one role of c-Abl may be to negatively regulate UV-DDB activity by phosphorylation of DDB2.

View details for DOI 10.1074/jbc.M204416200

View details for PubMedID 12107171

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Xeroderma pigmentosum complementation group E and UV-damaged DNA-binding protein.

Tang J, Chu G.

DNA Repair (Amst). 2002; 1 (8): 601-16  More 

              Abstract

UV-damaged DNA-binding protein (UV-DDB) is composed of two subunits, DDB1 (p127) and DDB2 (p48). Mutations in the DDB2 gene inactivate UV-DDB in individuals from complementation group E of xeroderma pigmentosum (XP-E), an autosomal recessive disease characterized by sun sensitivity, severe risk for skin cancer and defective nucleotide excision repair. UV-DDB is also deficient in many rodent tissues, exposing a shortcoming in rodent models for cancer. In vitro, UV-DDB binds to cyclobutane pyrimidine dimers (CPDs), 6-4 photoproducts and other DNA lesions, stimulating the excision of CPDs, and to a lesser extent, of 6-4 photoproducts. In vivo, UV-DDB plays an important role in the p53-dependent response of mammalian cells to DNA damage. When cells are exposed to UV, the resulting accumulation of p53 activates DDB2 transcription, which leads to increased levels of UV-DDB. Binding of UV-DDB to CPDs targets these lesions for global genomic repair, suppressing mutations without affecting UV survival. Apparently, cells are able to survive with unrepaired CPDs because of the activity of bypass DNA polymerases. Finally, there is evidence that UV-DDB may have roles in the cell that are distinct from DNA repair.

View details for DOI 10.1016/S1568-7864(02)00052-6

View details for PubMedID 12509284

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Xeroderma pigmentosum p48 gene enhances global genomic repair and suppresses UV-induced mutagenesis. 

Tang JY, Hwang BJ, Ford JM, Hanawalt PC, Chu G.

Mol Cell. 2000; 5 (4): 737-44  More 

              Abstract

UV-damaged DNA-binding activity (UV-DDB) is deficient in some xeroderma pigmentosum group E individuals due to mutation of the p48 gene, but its role in DNA repair has been obscure. We found that UV-DDB is also deficient in cell lines and primary tissues from rodents. Transfection of p48 conferred UV-DDB to hamster cells, and enhanced removal of cyclobutane pyrimidine dimers (CPDs) from genomic DNA and from the nontranscribed strand of an expressed gene. Expression of p48 suppressed UV-induced mutations arising from the nontranscribed strand, but had no effect on cellular UV sensitivity. These results define the role of p48 in DNA repair, demonstrate the importance of CPDs in mutagenesis, and suggest how rodent models can be improved to better reflect cancer susceptibility in humans.

View details for DOI 10.1016/S1097-2765(00)80252-X

View details for PubMedID 10882109

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Inhibition of lecithin-cholesterol acyltransferase and modification of HDL apolipoproteins by aldehydes. 

McCall MR, Tang JY, Bielicki JK, Forte TM.

Arterioscler Thromb Vasc Biol. 1995; 15 (10): 1599-606   More 

Experimental evidence suggests that aldehydes generated as a consequence of lipid peroxidation may be involved in the pathogenesis of atherosclerosis. It is well documented that aldehydes modify LDL: however, less is known concerning the effects of aldehydes on other plasma and interstitial fluid components. In the present study, we investigated the effects of five physiologically relevant aldehydes (acetaldehyde, acrolein, hexanal, 4-hydroxynonenal [HNE], and malondialdehyde [MDA]) on two key constituents of the antiatherogenic reverse cholesterol transport pathway, lecithin-cholesterol acyltransferase (LCAT) and HDL. Human plasma was incubated for 3 hours at 37 degrees C with each one of the five aldehydes at concentrations ranging from 0.16 to 84 mmol/L. Dose-dependent decreases in LCAT activity were observed. The short-chain (acrolein) and long-chain (HNE) alpha,beta-unsaturated aldehydes were the most effective LCAT inhibitors. Micromolar concentrations of these unsaturated aldehydes resulted in significant reductions in plasma LCAT activity. The short- and longer-chain saturated aldehydes acetaldehyde and hexanal and the dialdehyde MDA were considerably less effective at inhibiting LCAT than were acrolein and HNE. In addition to inhibiting LCAT, aldehydes increased HDL electrophoretic mobility and cross-linked HDL apolipoproteins. Cross-linking of apolipoproteins A-I and A-II required higher aldehyde concentrations than inhibition of LCAT. The alpha,beta-unsaturated aldehydes acrolein and HNE were fourfold to eightfold more effective cross-linkers of apolipoproteins A-I and A-II than the other aldehydes studied. These data suggest that products of lipid peroxidation, especially unsaturated aldehydes, may interfere with normal HDL cholesterol transport by inhibiting LCAT and modifying HDL apolipoproteins.

View details for DOI 10.1161/01.ATV.15.10.1599

View details for PubMedID 7583533

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