Abstract 4374: CE+BZA combination therapy decreases breast cancer outgrowth in part through activation of the AHR pathway

Abstract

Abstract Menopause occurs in all women, usually between the ages of 45 and 55. As a result of menopause, women often experience undesirable vasomotor symptoms, which can be alleviated by hormone replacement therapy (HRT). The Women's Health Initiative (WHI) trial concluded that PremPro, a HRT formulation that combines conjugated equine estrogens (CE) with medroxyprogesterone acetate, increases the risk of breast cancer. Over the years, the number of women taking HRT has dramatically decreased due to the perceived risk based largely on the results of the WHI trial. Follow-up studies suggest that breast cancer cases from PremPro treatment were primarily due to the outgrowth of occult tumors, not the formation of new disease. Duavee, a more recent form of HRT that combines CE and bazedoxifene (BZA), a selective estrogen receptor modulator (SERM) and degrader (SERD), has been approved by the FDA for treatment of moderate to severe hot flashes and to reduce the risk of osteoporosis. More importantly, this CE+BZA mixture not only relieves symptoms associated with menopause, but it also does not stimulate the breast or uterus. Several preclinical studies suggest that CE+BZA might be protective in the breast, however the mechanism of action of this new combination therapy is not known. Our goal, therefore, was to elucidate the underlying molecular mechanisms by which CE+BZA differentially affects estrogen receptor alpha (ERα) action in the mammary gland. Pathway analysis from RNA-sequencing revealed Aryl Hydrocarbon Receptor (AHR) signaling as the top canonical pathway affected by treatment with CE+BZA. Previous studies reported that 4-hydroxytamoxifen, a metabolite of the SERM tamoxifen, was able to activate the AHR pathway. In our study we determined that BZA treatment activated the AHR pathway in both ERα-positive and ERα-negative cell lines. BZA increased expression of aryl hydrocarbon receptor repressor (AHRR) in cell lines and increased expression of two AHR pathway members, CYP1A1 and CYP1B1, in tumors of estrogen-sensitive polyoma middle T antigen (PyMT) mice. AHRR has been reported to act as a tumor suppressor in breast cancer; therefore activation of AHR by BZA in women taking CE+BZA combination therapy might be one mechanism by which outgrowth of occult tumors is decreased. Further evaluation of the role of AHR in breast cancer is necessary to improve our understanding of CE+BZA action. Citation Format: Anna G. Dembo, Emily S. Aledort, Geoffrey L. Greene. CE+BZA combination therapy decreases breast cancer outgrowth in part through activation of the AHR pathway [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4374.