Journal of Endocrinology, 2013, 218(1):135-49.

Repression of mammary adipogenesis by genistein limits mammosphere formation of human MCF-7 cells

Maria Theresa E Montales, Omar M Rahal, Hajime Nakatani, et al

Arkansas Children's Nutrition Center, Departments of Pediatrics, Physiology and Biophysics, University of Arkansas for Medical Sciences, 15 Children's Way, Little Rock, Arkansas 72202, USA

Mammary adipose tissue may contribute to breast cancer development and progression by altering neighboring epithelial cell behavior and phenotype through paracrine signaling. Dietary exposure to soy foods is associated with lower mammary tumor risk and reduced body weight and adiposity in humans and in rodent breast cancer models. Despite the suggested linkage between obesity and breast cancer, the local influence of bioactive dietary components on mammary adiposity for antitumor effects remains unknown. Herein, we report that post-weaning dietary exposure to soy protein isolate and its bioactive isoflavone genistein (GEN) lowered mammary adiposity and increased mammary tumor suppressor PTEN and E-cadherin expression in female mice, relative to control casein diet. To ascertain GEN's role in mammary adipose deposition that may affect underlying epithelial cell phenotype, we evaluated GEN's effects on SV40-immortalized mouse mammary stromal fibroblast-like (MSF) cells during differentiation into adipocytes. MSF cells cultured in a differentiation medium with 40 nM GEN showed reductions in mature adipocyte numbers, triglyceride accumulation, and Pparγ (Pparg) and fatty acid synthase transcript levels. GEN inhibition of adipose differentiation was accompanied by increased estrogen receptor β (Erβ (Esr2)) gene expression and was modestly recapitulated by ERβ-selective agonist 2,3-bis-(4-hydroxyphenyl)-propionitrile (DPN). Reduction of Erβ expression by siRNA targeting increased Pparγ transcript levels and stromal fibroblast differentiation into mature adipocytes; the latter was reversed by GEN but not by DPN. Conditioned medium from GEN-treated adipocytes diminished anchorage-independent mammosphere formation of human MCF-7 breast cancer cells. Our results suggest a mechanistic pathway to support direct regulation of mammary adiposity by GEN for breast cancer prevention.

英国《内分泌学杂志》，2013年6月

由金雀异黄素对乳腺脂肪分化的抑制限制了人体 MCF-7乳腺球群细胞的形成

玛丽亚  特蕾莎 E 蒙泰勒斯，奥马尔  M 拉哈尔，中谷肇，等

美国阿肯色医科大学儿科、 生理学和生物物理学院阿肯色州儿童营养中心

乳腺脂肪组织可能有利于乳腺癌的发展和进展，通过改变相邻的上皮细胞行为和通过旁分泌信号传导的表型。大豆膳食与人体和啮齿类动物的乳房癌模型的较低的乳腺肿瘤发病风险、体重减少和肥胖症相关联。尽管提出了肥胖与乳腺癌之间的联系，生物活性膳食成分对乳腺肥胖的局部影响的抗肿瘤作用仍然未知。这里，我们报道了在雌性小鼠断奶后以大豆蛋白分离物及其生物活性异黄酮金雀异黄素 (GEN) 降低了乳腺肥胖症并提高乳腺肿瘤抑制基因 PTEN 和 E-钙粘蛋白表达，与对照样酪蛋白饮食相比。为了确认GEN在乳腺脂肪沉积可能会影响潜在的上皮细胞表型的作用，我们评估了GEN对SV40-永生小鼠乳腺间质成纤维细胞样 (MSF) 细胞在向脂肪细胞分化的过程中发挥的作用。用 40 nM GEN在分化培养基中培养的MSF细胞表现出成熟脂肪细胞数量、 甘油三酯积累以及激活受体和脂肪酸合酶转录水平减少。GEN抑制了脂肪分化，同时增加了雌激素受体 β （Erβ (Esr2)） 基因的表达，并且被选择性 ERβ 受体激动剂DPN适度重现。由siRNA 靶向减少的ERβ 表达增加了激活受体的转录水平并促进间质成纤维细胞分化为成熟脂肪细胞；后者被GEN逆转但不受 DPN影响。在人体乳腺癌细胞 MCF-7中，GEN处理的脂肪细胞的条件培养液减少了锚固独立乳腺球群细胞的形成。我们的结果表明机械式通路，以支持GEN对乳腺肥胖的直接调节用于预防乳腺癌。