Genistein‐mediated inhibition of mammary stromal adipocyte differentiation limits expansion of mammary stem/progenitor cells by paracrine signaling

Abstract

Mammary adiposity may contribute to breast cancer development and progression by releasing cytokines and other inflammatory mediators that promote mammary epithelial proliferation. We evaluated the effects of soy isoflavone genistein (GEN) on the adipogenic differentiation of a SV40‐immortalized mouse mammary stromal fibroblast like cells (MSF) treated with differentiating agents insulin, hydrocortisone and troglitazone (DM). MSF cultured in DM with and without extracellular matrix for 14 days showed reduced differentiation (2–3 fold) into mature adipocytes with 40nM but not 2uM GEN, as evaluated by Oil Red O staining. Addition of sera from GEN‐fed adult mice to MSF similarly reduced adipogenic differentiation (4–5 fold), relative to sera from casein‐fed mice. Lipid accumulation was decreased by GEN (40nM>2uM). Expression levels of lipogenic enzyme genes fatty acid synthase and PPAR‐γ were down‐regulated by 40nM GEN. Estrogen receptor (ER)‐β, an inhibitor of PPAR‐γ transcriptional activity, but not ER‐α transcript levels were increased by 40 nM GEN. Conditioned media from GEN‐treated MSF reduced anchorage‐independent mammosphere formation of human breast cancer cells MCF‐7. Thus, dietary factor control of mammary adiposity, possibly mediated by ER‐β, may limit mammary stem/progenitor cell expansion and protect against breast cancer.Grant Funding Source: USDA‐CRIS 6251‐5100002‐06S; CUMG/ACHRI