Paracrine-Acting Adiponectin Promotes Mammary Epithelial Differentiation and Synergizes with Genistein to Enhance Transcriptional Response to Estrogen Receptor β Signaling

Mammary stromal adipocytes constitute an active site for the synthesis of the adipokine, adiponectin (APN) that may influence the mammary epithelial microenvironment. The relationship between local, mammary tissue-derived APN and breast cancer risk is poorly understood. Here, we identify a novel mechanism of APN-mediated signaling that influences mammary epithelial cell proliferation, differentiation, and apoptosis to modify breast cancer risk. We demonstrate that early dietary exposure to soy protein isolate induced mammary tissue APN production without corresponding effects on systemic APN levels. In estrogen receptor (ER)-negative MCF-10A cells, recombinant APN promoted lobuloalveolar differentiation by inhibiting oncogenic signal transducer and activator of transcription 3 activity. In ER-positive HC11 cells, recombinant APN increased ER beta expression, inhibited cell proliferation, and induced apoptosis. Using the estrogen-responsive 4X-estrogen response element promoter-reporter construct to assess ER transactivation and small interfering RNA targeting of ER alpha and ER beta, we show that APN synergized with the soy phytoestrogen genistein to promote ER beta signaling in the presence of estrogen (17 beta-estradiol) and ER beta-specific agonist 2,3-bis(4-hydroxyphenyl)-propionitrile and to oppose ER alpha signaling in the presence of the ER alpha-specific agonist 4,4',4'-(4-propyl-(1H)-pyrazole-1,3,5-triyl)trisphenol. The enhancement of ER beta signaling with APN + genistein cotreatments was associated with induction of apoptosis, increased expression of proapoptotic/prodifferentiation genes (Bad, p53, and Pten), and decreased antiapoptotic (Bcl2 and survivin) transcript levels. Our results suggest that mammary-derived APN can influence adjacent epithelial function by ER-dependent and ER-independent mechanisms that are consistent with reduction of breast cancer risk and suggest local APN induction by dietary factors as a targeted approach for promotion of breast health. (Endocrinology 152: 3409-3421, 2011)