Menopause occurs in all women, typically between the ages of 45 and 55. As a result of menopause, women often experience undesirable symptoms such as hot flashes, vaginal dryness and atrophy, and osteoporosis. These symptoms can be alleviated with 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 mainly 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 undetectable 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 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 endometrium. 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, is to elucidate the underlying molecular mechanisms by which CE+BZA differentially affects estrogen receptor alpha (ER) action in the mammary gland, using transcriptome and cistrome analysis in breast cancer cell lines. RNA-Seq and ChIP-Seq studies suggest that CE+BZA increases pathways related to cell death and decreases activation of pathways related to cell proliferation and survival. BZA was found to exert its action through the aryl hydrocarbon receptor (AHR) pathway, further clarifying the role of AHR in breast cancer. We are also studying the effects of CE+BZA on early mammary cancer progression in the estrogen-sensitive polyoma middle T antigen (PyMT) transgenic mouse model and have observed that treatment with CE+BZA delayed the onset of tumors and decreased their rate of growth. Mice treated with CE+BZA also survived longer. In addition, CE+BZA was able to decrease the rate of tumor growth in an ER-positive patient-derived xenograft (PDX) mouse model. 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 and for physicians prescribing it.