Obesity is a risk factor for postmenopausal estrogen receptor alpha (ERa)-positive (ER þ) breast cancer. Molecular mechanisms underlying factors from plasma that contribute to this risk and how these mechanisms affect ERa signaling have yet to be elucidated. To identify such mechanisms, we performed whole metabolite and protein profiling in plasma samples from women at high risk for breast cancer, which led us to focus on factors that were differentially present in plasma of obese versus nonobese postmenopausal women. These studies, combined with in vitro assays, identified free fatty acids (FFA) as circulating plasma factors that correlated with increased proliferation and aggressiveness in ER þ breast cancer cells. FFAs activated both the ERa and mTOR pathways and rewired metabolism in breast cancer cells. Pathway preferential estrogen-1 (PaPE-1), which targets ERa and mTOR sig-naling, was able to block changes induced by FFA and was more effective in the presence of FFA. Collectively, these data suggest a role for obesity-associated gene and metabolic rewiring in providing new targetable vulnerabilities for ER þ breast cancer in postmenopausal women. Furthermore, they provide a basis for preclinical and clinical trials where the impact of agents that target ERa and mTOR signaling cross-talk would be tested to prevent ER þ breast cancers in obese postmenopausal women. Significance: These findings show that obesity-associated changes in certain blood metabolites rewire metabolic programs in cancer cells, influence mammary epithelial cell tumorigenicity and aggressiveness, and increase breast cancer risk.

Obesity is a potential risk for several cancers, including postmenopausal, hormone dependent breast cancers. In this review, we will summarize recent studies on the impact of obesity on postmenopausal women’s health and discuss several mechanisms that were proposed to increase the risk of breast carcinogenesis.

A 70-year-old male patient with a myocardial infarction, 3 months previously, happened to be wearing a Holter monitor at cardiac arrest during micturition. The patient had ventricular fibrillation (VF) and was successfully resuscitated by means of defibrillation. Analysis of the Holter tape revealed atrial fibrillation and secondary ventricular premature beats (VPB), i.e., VPBs dependent upon a relatively long interval between the two preceding heartbeats. The VF was preceded by an especially long R-R interval (1.45 sec) following a run of especially short R-R intervals implying the sharpest deceleration of the ventricular rate during 1 hour Holter recording preceding the cardiac arrest. A peculiar large alteration of the T wave configuration was also found to precede the VF.