Estrogen receptor and mTOR signaling rewires cancer metabolism in obesity-associated breast cancer

Obesity is a risk factor for postmenopausal ERα (+) breast cancer. Molecular mechanisms activated by the factors from serum that contribute to this risk and how these mechanisms affect ERα signaling are yet to be elucidated. To identify such mechanisms, we performed whole metabolite and protein profiling in serum samples, which enabled us to focus on factors that were differentially present in serum from cancer-free vs. breast cancer susceptible and obese vs. non-obese post-menopausal women. These studies combined with in vitro assays identified free fatty acids (FFAs), as serum factors that correlate with increased proliferation and aggressiveness in ERα(+) breast cancer cells by. FFAs activated both ERα and mTOR pathways and rewired metabolism in breast cancer cells. Pathway preferential estrogen-1 (PaPE-1), which target ERα 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 ERα-(+) 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 properties of breast tumors in obese postmenopausal women. Data set 1 (6 samples): For gene expression analysis, total RNA was extracted from 3 biological replicates for each ligand treatment using Trizol reagent and further cleaned using the RNeasy kit (QIAGEN). MCF-7 cells were treated with Veh (0.1% EtOH), 100 nM oleic acid (OA) in presence or absence of 1 μM PaPE-1 for 24 h. Once the sample quality and replicate reproducibility were verified, 2 samples from each group were subjected to sequencing. Data set 2 (15 samples): For gene expression analysis, total RNA was extracted from 3 biological replicates for each ligand treatment using Trizol reagent and further cleaned using the RNAeasy kit (QIAGEN). MCF-7 cells were treated with Veh (0.1% EtOH) or 100 nM OA, LA, PA or SA for 24 h. Once the sample quality and replicate reproducibility were verified, 2 samples from each group were subjected to sequencing.