11/8/2023 0 Comments Incontrol vs rewired![]() ![]() One of these compounds, termed pathway preferential estrogen 1 (PaPE-1), was initially identified in a screen of estrogen-like molecules that had lower affinity for the estrogen receptor, and stimulated extranuclear ER activity with limited effects on nuclear ER-target gene expression. We have previously described the identification and design of novel pathway preferential estrogens that modulate ERα and mTOR signaling cross-talk ( 14). Using a multiple -omics approach, we identified certain free fatty acids (FFA) that are relevant to obesity-associated breast cancer risk and uncovered ERα and mTOR pathway–dependent metabolic rewiring in breast cancer cells under conditions that mimic plasma from obese postmenopausal women. ![]() ![]() Our hypothesis was that specific circulating metabolites and proteins, detectable in plasma, increase the risk of ER + breast cancer in obese postmenopausal women compared with their nonobese counterparts. Our aim in this study was to identify and test the impact of various circulating factors in blood associated with breast cancer risk. ![]() Obesity-associated cancers are a significant clinical problem and uncovering and targeting obesity-associated molecules and signaling pathways activated by these molecules may identify populations at risk and reduce breast cancer–related deaths. Eighty-two different studies including analysis of more than 200,000 women with breast cancer showed that obesity increases mortality both in premenopausal and postmenopausal women ( 8). Being overweight after menopause increases ER + breast cancer risk by 70% ( 5–7). A weight gain of 55 or more pounds from age 18 increases breast cancer risk by 50% ( 4). In fact, almost 70% of postmenopausal women in the United States are overweight or obese. Sedentary lifestyle and western-style, fat- and sugar-rich diets, combined with low estrogen levels in postmenopausal women, aggravate this problem, making postmenopausal women more susceptible to weight gain, fat redistribution to abdominal areas, dyslipidemia, hypertension, and insulin resistance, which are the major hallmarks of metabolic syndrome ( 3). The rate of increase in BMI is higher for women in the United States and percent of cancer cases attributable to excess body weight is twice as high for women compared with men ( 1, 2). Furthermore, they provide a basis for preclinical and clinical trials where the impact of agents that target ERα and mTOR signaling cross-talk would be tested to prevent ER + breast cancers in obese postmenopausal women. Collectively, these data suggest a role for obesity-associated gene and metabolic rewiring in providing new targetable vulnerabilities for ER + breast cancer in postmenopausal women. Pathway preferential estrogen-1 (PaPE-1), which targets ERα and mTOR signaling, was able to block changes induced by FFA and was more effective in the presence of FFA. FFAs activated both the ERα and mTOR pathways and rewired metabolism in breast cancer cells. 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 + breast cancer cells. 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. Molecular mechanisms underlying factors from plasma that contribute to this risk and how these mechanisms affect ERα signaling have yet to be elucidated. Obesity is a risk factor for postmenopausal estrogen receptor alpha (ERα)-positive (ER +) breast cancer. ![]()
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |