Abstract 1802: ER-positive breast cancer prevention with the use of hormone replacement therapy

Abstract

Abstract Menopause occurs in women between the ages of 45 and 55 and often results in undesirable vasomotor symptoms. Hormone replacement therapy (HRT) alleviates these symptoms, including hot flashes, difficulty sleeping, fatigue, and vaginal atrophy. HRT also prevents osteoporosis. PremPro, a currently available HRT formulation that combines conjugated equine estrogens (CE) with medroxyprogesterone acetate, increases the risk of breast cancer. Due to the perceived risk based largely on the results of the Women's Health Initiative (WHI) trial, the number of women taking HRT has decreased dramatically. Duavee, a new form of HRT that combines CE and bazedoxifene (BZA), a selective estrogen receptor modulator (SERM) and degrader (SERD), has recently been approved by the FDA for treatment of moderate to severe hot flashes and to reduce the risk of osteoporosis. Importantly, this CE/BZA mixture not only relieves symptoms associated with menopause, but it also does not stimulate the breast or uterus. Although several preclinical studies suggest that CE/BZA might be protective in the breast, the mechanism of action of this new combination therapy is not known. Our goal, therefore, is to elucidate the underlying molecular mechanisms by which CE/BZA differentially affects estrogen receptor alpha (ERα) action in the mammary gland, using transcriptome and whole genome occupancy analysis in breast cancer cell lines. We are also studying the effects of CE/BZA on early mammary cancer progression in the polyoma middle T antigen (PyMT) transgenic mouse model, which has been shown to be sensitive to estrogens. In addition, we are studying the effects in an ERα-positive patient-derived xenograft mouse model. We have determined that CE modulates gene expression in MCF7 cells similar to 17β-estradiol (E2), and that BZA is able to inhibit these effects. We have also observed that CE increases ERα occupancy versus E2 at response elements associated with some estrogen target genes, whereas CE/BZA decreases this occupancy. In the PyMT mouse model, we have determined that CE/BZA significantly delays the onset of mammary tumors in ovariectomized mice and prolongs their survival when compared to E2 and CE treatment alone. An improved understanding of the molecular mechanisms of CE/BZA action in hormone sensitive breast cancer cell and animal models should have important implications for women considering HRT. Citation Format: Anna G. Dembo, Geoffrey L. Greene. ER-positive breast cancer prevention with the use of hormone replacement therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1802.