Location: Arkansas Children's Nutrition CenterTitle: Paracrine-acting adiponectin promotes mammary epithelial differentiation and synergizes with genistein to enhance transcriptional response to estrogen receptor beta signaling Author
Submitted to: Endocrinology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/7/2011
Publication Date: 9/1/2011
Citation: Rahal, O., Simmen, R.C. 2011. Paracrine-acting adiponectin promotes mammary epithelial differentiation and synergizes with genistein to enhance transcriptional response to estrogen receptor beta signaling. Endocrinology. 152(9):3409-3421. Interpretive Summary: The mammary gland is composed of an epithelial tree surrounded by a mammary fat pad mainly composed of adipocytes, endothelial cells and inflammatory cells. Adiponectin is a protein synthesized by adipocytes and its serum levels have been inversely related to breast cancer. In the present study, we showed that dietary intake of soy protein increases adiponectin expression in the mammary tissue. Using mammary epithelial cells, we also showed that adiponectin can decrease cell proliferation and increase cell death and thus enhance differentiation to prevent dysregulation of cell growth that may lead to cancer. We also demonstrated that adiponectin can act together with soy isoflavone genistein to enhance activity of estrogen receptor beta, which has been demonstrated to be a tumor suppressor in breast cancer. Thus by induction of estrogen receptor beta signaling by adiponectin in combination with genistein, suggest that dietary induction of local adiponectin in the mammary tissue can have beneficial effects to breast health.
Technical Abstract: 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. Herein, 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 (SPI) 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 (STAT3) activity. In ER-positive HC11 cells, recombinant APN increased ER beta expression, inhibited cell proliferation, and induced apoptosis. Using the estrogen-responsive 4X-ERE promoter-reporter construct to assess ER transactivation and siRNA targeting of ER alpha and ER beta, we show that APN synergized with the soy phytoestrogen genistein (GEN) to promote ER beta signaling in the presence of estrogen (E2) and ER beta specific agonist DPN and to oppose ER alpha signaling in the presence of the ER alpha specific agonist PPT. The enhancement of ER beta signaling with APN+GEN co-treatments was associated with induction of apoptosis, increased expression of pro-apoptotic/pro-differentiation genes (Bad, p53, Pten) and decreased anti-apoptotic (Bcl2, survivin) transcript levels. Our results suggest that mammary-specific APN can influence adjacent epithelial function by ER-dependent and -independent mechanisms that are consistent with reduction of breast cancer risk and suggest local APN induction by dietary factors as a targeted strategy for promotion of breast health.