Lefty may offer a right way to treat breast cancers

Professor Michael Clarke, MD

July 28, 2020

Researchers at the Stanford Institute for Stem Cell Biology and Regenerative Medicine have discovered a molecule that can fuel the growth of breast cancer cells. This discovery may offer a new avenue for attacking breast cancer, which may be especially useful for “triple negative” breast cancers that don’t currently offer a good target for therapy, they say.

 The molecule, called LEFTY1 by the researchers, plays a role in normal breast tissue remodeling that happens in response to changing hormonal cycles, but in can also be used to promote out of control growth in breast cancer cells. “A normal function of this molecule has been hijacked by the cancer cells to allow them to replicate unchecked,” said institute associate director Michael Clarke, MD. 

LEFTY1 inhibits other molecules that change stem cells into more mature or “differentiated” cells. As cells mature, they lose their ability to make more of themselves. “What we discovered is that when stem and progenitor cells are stopped from specializing, they default to a program of reproducing themselves,” said Neethan Lobo, PhD, a co-lead author on the paper and a former postdoctoral scholar in the Clarke lab.  “It’s like if you stopped someone from becoming an adult, they stay a kid forever.”

Two facts about LEFTY1 make it very exciting for researchers. “One thing we saw is that the tumor initiating cells, sometimes called cancer stem cells, are exquisitely dependent on this molecule,” Lobo said. The researchers found that when they blocked the signal from LEFTY1, tumor initiating cells in triple negative breast cancer tissue would stop growing.

The other exciting thing is that LEFTY1 is a molecule that affects cellular activity from outside the cell. “A lot of things we look at are inside the cell, and are therefore not easily manipulated,” said Jane Antony, PhD, a co-lead author on the paper and a postdoctoral scholar in the Clarke lab. “But this is released outside the cells, which makes it much more accessible to drugs and therapies we might administer.”

The paper was published in the journal Cell Stem Cell on July 20, 2020. Clarke is the senior author on the paper. Antony, Lobo and former instructor in the Clarke lab Maider Zabala, PhD, are co-lead authors. Assistant professor of biomedical data science Aaron Newman, PhD, as a member of the institute, also contributed to the research. 

The work was supported by the National Institutes of Health (U01CA154209-01and P01 CA139490-05), the Department of Defense (W81XWH-13-1-0281 and W81XWH-11-1-0287), the Ludwig Fund for Cancer Research, the Fulbright Foundation, the Susan G. Komen for the Cure/Princess Cruises Community Foundation, the Breast Cancer Research Foundation, the Alfonso Matin-Escudero Foundation, and the Chan Zuckerberg Initiative.