The mystery of why the risk of breast cancer goes up in women whose first pregnancies occur after the age of 35 may boil down to a single factor called STAT5, according to a new study led by researchers from Baylor College of Medicine slated to appear today in the online journal eLife.
This work was directed by Dr. Yi Li, associate professor in the Lester and Sue Smith Breast Center at BCM. Li explained that pregnancy is strongly associated with breast cancer risk, but depending on the age of the woman the effects are in the opposite direction.
Early first pregnancy protects while late first pregnancy above age 35 increases breast cancer risk. But how can a woman’s first pregnancy have such a different effect on later breast cancer risk depending on her age at the time of her pregnancy?
This contradictory result has confused researchers for years, but new data from Li’s laboratory provides a potential explanation that also offers a new strategy for breast cancer prevention.
They knew that the hormones of pregnancy and lactation cause growth of the breast, in part by activating the STAT5 protein, and that after weaning the STAT5 protein activity in normal breast cells largely disappears and many of the cells undergo a programmed breakdown called apoptosis which had been held in check by STAT5.
This post-weaning remodeling of the breast leaves the cells less likely to multiply and thus less likely to acquire cancer-causing mutations – hence the protective effect of pregnancy in younger women.
But in women who are older before their first pregnancy, more cells may have already acquired cancer-causing mutations that may allow them to retain active STAT5, escape apoptosis, and develop into breast cancer.
The group’s studies in mice confirmed their hypothesis that pre-cancerous lesions often retained their pregnancy-caused STAT5 activation even after weaning and thus continued growing after normal cells had ceased, frequently leading to cancers.
“You have a persistent survival signal that allows the lesion to expand,” said Li. “With a larger lesion, the risk of breast cancer increases.”
But they also found that after weaning, a short course of a drug that inhibits STAT5 allowed normal apoptosis of these cells and greatly reduced the development of cancers. This suggests the exciting possibility that a similar short treatment with a STAT5 inhibitor after a woman’s late first pregnancy might be able to eliminate the extra risk of breast cancer.
Indeed, if such a treatment allows apoptosis of potential pre-cancerous lesions, it could help other women at high risk of breast cancer – current prevention for such women requires years-long antiestrogenic treatments that may still be ineffective against some types of breast cancer.
As a first test of this possibility, Li and his colleagues are already planning a study in women with ductal carcinoma in situ or early premalignant breast lesions who are scheduled for surgery. They will give a STAT5 inhibitor for two weeks and then evaluate the breast tissue after surgery to determine if the women responded. The results of this study might open the door to a larger trial and a new approach to breast cancer prevention.
Others who took part in this work include Svasti Haricharan; Jie Dong; Sarah Hein; Jay Reddy; Zhijun Du; Michael Toneff; Kimberly Holloway;Susan Hilsenbeck; Shixia Huang; Carolina Gutierrez; C. Kent Osborne and David Tweardy, all of BCM, Hong Zhang, Rachel Atikinson and Wendy Woodward, all of the University of Texas MD Anderson Cancer Center, and Sonali Jindal, Virginia Borges and Pepper Schedin, all of the University of Colorado Denver.
Funding for this work came from Congressionally Directed Medical Research Programs (Grants BC073703, BC083190, and BC085050), the National Institutes of Health (Grants CA113869, CA124820, CA149783, CA153659, U54CA149196, P30CA125123, P50CA058183, and T32AG000183), the Nancy Owens Memorial Foundation, and the Cancer Prevention and Research Institute of Texas (Grant RP100421).