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

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.

Estrogen Receptor α and β in Mouse: Adipose-Derived Stem Cell Proliferation, Migration, and Brown Adipogenesis In Vitro

“…In contrast, ERα induces UCP-1, PGC-1α, and PPAR-γ expression, and, thus, may improve brown adipogenesis. Although a former study showed similar effects of ERβ [27], our work explains and compares the effect of ERα in more detail. Taken together, our results and that of Montales et al concerning brown adipogenesis might be the basis to further investigate if this ERβ-mediated effect is usable as treatment option in obesity, i.e increasing BAT and consequently increasing cellular energy consumption.…”

Apoptotic Death of Cancer Stem Cells for Cancer Therapy

“…Soy isoflavone genistein and blueberry polyphenolic acids repress mammosphere formation of breast cancer cells [84,85], and 20 (s)-ginsenoside Rg3 inhibits proliferation of colon CSCs and induces apoptosis through caspase-9 and caspase-3 pathways [86]. NV-128 is an isoflavone derivative that targets mitochondria of CD44+/MyD88+ ovarian CSCs and induce apoptosis by promoting a status of cellular starvation, which activates two independent pathways: the AMPKα1 pathway that causes mTOR inhibition and the mitochondrial MAP/ERK pathway that leads to loss of mitochondrial membrane potential [87].…”

Anticarcinogenecity of microbiota and probiotics in breast cancer

“…[57] Breast cancer prevention by genistein was linked with regulation of breast adiposity. [58] Role of folate or folic acid is still controversial and is investigated both in animal models and breast cancer patients. Some of the epidemiological studies showed inverse relationship between folic acid consumption and breast cancer risk.…”