|Montales, Maria Theresa -|
|Rahal, Omar -|
|Nakatani, Hajime -|
|Matsuda, Tsukasa -|
|Simmen, Rosalia -|
Submitted to: Journal of Endocrinology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: May 3, 2013
Publication Date: July 1, 2013
Citation: Montales, M.E., Rahal, O.M., Nakatani, H., Matsuda, T., Simmen, R.C. 2013. Repression of mammary adipogenesis by genistein limits mammosphere formation of human MCF-7 cells. Journal of Endocrinology. 218(1):135-149. Interpretive Summary: Obese women have a high risk for breast cancer. Intake of soy foods have been known to decrease the risk of breast cancer in animal models of the disease. It is also known that soy can reduce the size of fat depots in mice and humans. In this study, we determined whether genistein, a component of soy foods, can inhibit the growth and differentiation of fat cells specifically in the mammary gland. We found that genistein reduced the size of mammary fat cells and their ability to produce lipids. In addition, components secreted by fat cells inhibited the growth of mammary cells that give rise to tumors. Our studies demonstrate that mammary fat cells may contribute to breast cancer and that components in foods may prevent breast cancer by acting on fat cells.
Technical Abstract: 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 Pparg (Pparg) and fatty acid synthase transcript levels. GEN inhibition of adipose differentiation was accompanied by increased estrogen receptor b(Erb (Esr2)) gene expression and was modestly recapitulated by ERb-selective agonist 2,3-bis-(4-hydroxyphenyl)-propionitrile (DPN). Reduction of Erb expression by siRNA targeting increased Pparg 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.