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.
J Endocrinol. 2013 Jun 1;218(1):135-49. doi: 10.1530/JOE-12-0520. Print 2013 Jul.
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.
乳腺脂肪组织可能通过旁分泌信号改变邻近上皮细胞的行为和表型，从而促进乳腺癌的发生和发展。人类和啮齿动物乳腺癌模型中，饮食暴露于大豆食品与降低乳腺癌风险、降低体重和体脂有关。尽管肥胖与乳腺癌之间存在关联，但生物活性膳食成分对乳腺脂肪的局部影响对于抗肿瘤作用仍然未知。在此，我们报告称，相对于对照酪蛋白饮食，断奶后饮食暴露于大豆分离蛋白及其生物活性异黄酮染料木黄酮（GEN）可降低雌性小鼠的乳腺脂肪含量，并增加乳腺肿瘤抑制因子 PTEN 和 E-钙黏蛋白的表达。为了确定 GEN 在可能影响潜在上皮细胞表型的乳腺脂肪沉积中的作用，我们评估了 GEN 在 SV40 永生化的小鼠乳腺基质成纤维细胞样（MSF）细胞分化为脂肪细胞过程中的作用。在含有 40 nM GEN 的分化培养基中培养的 MSF 细胞显示成熟脂肪细胞数量减少，甘油三酯积累减少，以及 Pparγ（Pparg）和脂肪酸合酶转录水平降低。GEN 抑制脂肪分化伴随着雌激素受体 β（Erβ（Esr2））基因表达增加，并且被 ERβ 选择性激动剂 2,3-双-（4-羟苯基）-丙腈（DPN）适度模拟。用靶向 Erβ 的 siRNA 降低 Erβ 表达会增加 Pparγ 转录水平，并促进基质成纤维细胞分化为成熟脂肪细胞；后者被 GEN 逆转，但不能被 DPN 逆转。用 GEN 处理的脂肪细胞的条件培养基减少了人 MCF-7 乳腺癌细胞的无锚定独立球体形成。我们的结果表明，通过 GEN 直接调节乳腺脂肪的机制途径支持乳腺癌的预防。
