Endocrinology, 2011, 152(9):3409-21.

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

Omar M Rahal and Rosalia C. M.Simmen

Interdisciplinary Biomedical Sciences Program, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72202, USA

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 ERβ 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 ERα and ERβ, we show that APN synergized with the soy phytoestrogen genistein to promote ERβ signaling in the presence of estrogen (17β-estradiol) and ERβ-specific agonist 2,3-bis(4-hydroxyphenyl)-propionitrile and to oppose ERα signaling in the presence of the ERα-specific agonist 4,4',4'-(4-propyl-(1H)-pyrazole-1,3,5-triyl)trisphenol. The enhancement of ERβ 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.

美国《内分泌学》，2011年9月

旁分泌-活化的脂联素促进乳腺上皮细胞的分化并且与染料木黄酮协同增强对雌激素受体信号的转录响应

奥马尔 米拉和罗萨莉娅 C M 西门

美国阿肯色医科大学跨学科生物医学科学项目

乳腺基质脂肪细胞被认为是合成脂肪因子脂联素 (APN)的活性位，而APN可能会影响乳腺上皮微环境。"局部"，乳腺组织衍生的 APN 和患乳腺癌的风险之间的关系的认知甚少。这里，我们确定了 APN 介导信号影响乳腺上皮细胞增殖、 分化和凋亡，进而减小患乳腺癌风险的新机制。我们证明，早期的膳食接触大豆蛋白分离物诱发了乳腺组织 APN 的产生但是没有系统性 APN 浓度的相应影响。在雌激素受体 (ER)-阴性 MCF-10A 细胞中，重组 APN 通过抑制致癌信号转导子和转录 3活性激活剂来促进小叶肺泡分化。在ER-阳性HC11细胞中，重组 APN提高了ERβ的表达，抑制细胞增殖，并诱导细胞凋亡。使用雌激素敏感的 4 X- 雌激素响应元素启动子报导基因构造来评估 ER 反式激活基因和小干扰 RNA 对ERα 和 ERβ的靶向性，我们发现当雌激素 （17β-雌二醇） 和ERβ特定受体激动剂 2,3-双(4-羟基苯基)-腈存在时， APN与大豆植物雌激素三羟异黄酮协同促进 ERβ 信号，进而反对在ERα特定受体激动剂4,4',4'-(4-丙基-(1H)-pyrazole-1,3,5-三基)三苯酚存在下的ERα 信号。用 APN + 金雀异黄素联合治疗增强 ERβ 信号与诱导细胞凋亡，增加凋亡/分化（Bad，p53 和 Pten）基因表达，并降低凋亡 （Bcl2 和生存蛋白） 转录水平等有关。我们的结果表明乳腺衍生APN 可以通过 ER 依赖性和 ER 独立机制影响相邻上皮细胞的功能，符合减少患乳腺癌的风险，并且表明由饮食因素诱导的局部 APN可以作为促进乳房健康的针对性方法。