Abstract 5044: Reducing breast cancer risk with hormone replacement therapy

Abstract

Abstract Menopause occurs in women between the ages of 45 and 55 and often results in symptoms that can be alleviated with hormone replacement therapy (HRT). HRT improves the symptoms associated with menopause that negatively affect quality of life, such as hot flashes, difficulty sleeping, fatigue, and vaginal atrophy. HRT also prevents osteoporosis. A current HRT formulation, which includes conjugated equine estrogens (CE) and medroxyprogesterone acetate, unfortunately increases the risk of breast cancer. Over the years, the number of women taking HRT has decreased due to this perceived increased risk. A new form of HRT, which contains CE and bazedoxifene (BZA), a selective estrogen receptor modulator, has recently been approved by the FDA for treatment of moderate to severe hot flashes and for the reduction of osteoporosis development. The CE/BZA mixture has been shown to not only relieve symptoms associated with menopause, but also does not stimulate the breast or uterus. Various studies show that CE/BZA may be protective in the breast. Currently, the mechanism of action of this new combination therapy is not known. Our goal is to identify the molecular mechanism of action of CE/BZA through transcriptome and whole genome occupancy analysis in breast cancer cell lines. In addition, we are determining the effects of the combination therapy on breast cancer progression in a transgenic mouse model. The overall hypothesis of our project is that the ability of CE/BZA to delay the onset of mammary tumors and decrease the number of lesions in the polyoma middle T antigen transgenic mouse model is due to its action as an estrogen receptor α antagonist in the mammary gland. We have determined that CE stimulates gene expression in MCF7 cells at a similar rate to 17β-estradiol, and that BZA is able to decrease this stimulation. Similarly, we have found that CE increases ERα occupancy at promoters of some estrogen target genes, while a combination of CE and BZA decreases this occupancy. Through understanding the molecular mechanism of CE/BZA and by determining whether it reduces the incidence of invasive breast cancer in a transgenic mouse model, we will be able to improve quality of life for many women by relieving menopausal symptoms in a safe manner. Citation Format: Anna Dembo, Geoffrey Greene. Reducing breast cancer risk with hormone replacement therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5044. doi:10.1158/1538-7445.AM2015-5044