Estrogen Receptor a (ERa)-mTOR signaling crosstalk rewires cancer cell metabolism providing a mechanism underlying obesity-associated postmenopausal breast cancer [RNA-seq]

Obesity is a risk factor for postmenopausal ERa (+) breast cancer. The metabolites from serum that contribute to this risk and how these factors affect ERa signaling are not known. Using whole metabolite profiling and a detection panel for proteins, we identified biomarkers that were differentially present in serum from obese vs. non-obese postmenopausal women, and we validated these factors in two separate cohorts of postmenopausal women who either developed breast cancer or those who were obese and lost weight after the onset of menopause. In vitro assays identified free fatty acids (FFAs), in particular oleic acid (OA) as serum factors that correlate with increased proliferation and aggressiveness in ERa(+) breast cancer cells by. FFAs activated both ERa and mTOR pathways and rewired metabolism in breast cancer cells. Pathway preferential estrogen-1 (PaPE-1), which target ERa and mTOR signaling, was able to block changes induced by FFAs. In fact, PaPEs were more effective in the presence of FFAs, suggesting a role for obesity-associated gene and metabolic rewiring in providing new targetable vulnerabilities for ERa-(+) breast cancer in postmenopausal women. Our findings provide a basis for preventing or inhibiting obesity-associated breast cancer by using PaPEs that would reverse these newly appreciated metabolic vulnerabilities of breast tumors in obese postmenopausal women. Overall design: Examination of metabolic pathways in MCF-7 cells upon OA exposure and PaPE-1 treatmnent