Abstract Obesity increases the risk of cancer death among postmenopausal women with estrogen receptor-positive (ER+) breast cancer, but the direct evidence for the mechanisms is lacking. The purpose of this study is to demonstrate direct evidence for the mechanisms mediating this epidemiologic phenomenon. Transcriptomic profiles of pretreatment biopsies from a prospective cohort of 137 ER+ breast cancer patients were analyzed. A transgenic and an orthotopic/syngeneic obese mouse models were created to phenocopy obese patients and evaluate the effect of obesity on breast carcinogenesis and tumor progression, and to explore further direct mechanisms. Functional transcriptomic analysis of untreated human ER+ breast cancer revealed that obesity was associated with increased insulin signaling among others. Many of the functional changes in obese patients were linked to cancer hallmarks. Obese mouse models recapitulated the functional transcriptomic landscape of obesity-associated changes seen in human ER+ breast cancer and demonstrated the role of the Akt/mTOR pathway in obesity-induced breast carcinogenesis and tumor progression. Functional transcriptomic analysis identified 85 biological functions common to humans and mice. An in vitro co-culture model revealed that adipocyte-secreted adipokines (e.g., TIMP-1) regulate adipocyte-induced breast cancer cell proliferation and invasion. The human transcriptomic data provided direct evidence for the roles of hyperinsulinemia, estrogen signaling, adipokine secretion, and inflammation in the link between obesity and ER+ breast cancer. Our animal experiments provide strong evidence for the causal relationship between obesity and accelerated carcinogenesis and cancer progression and for potential therapeutic interventions by blocking these signaling pathways. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-01-04.
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