Effect of genistein supplementation on microenvironment regulation of breast tumors in obese mice

Abstract

Obesity is an important risk factor for breast cancer in women before and after menopause. Adipocytes, key mediators in the tumor microenvironment, play a pivotal role in linking obesity with cancer. However, the potential of dietary components in modulating this link remains underexplored. Genistein, a soy-derived isoflavone, has shown promise in reducing breast cancer risk, attenuating obesity-associated inflammation, and improving insulin resistance. Yet, there are no reports examining whether genistein has the ability to reduce the breast tumor development effects of obesity. In this study, we constructed a mammary tumor model on ovariectomized obese mice and examined the effects of genistein on body condition and tumor growth. Meanwhile, the effects of genistein on tumor microenvironment were examined by experimental observation of peritumoral adipocytes and macrophages. In addition, we further investigated the effect of genistein on adipocyte and breast cancer cell crosstalk in co-culture experiments. Our findings indicate that dietary genistein significantly alleviates obesity, systemic inflammation, and metabolic disorders induced by a high-fat diet in ovariectomized mice. Notably, it also inhibits tumor growth in vivo. Genistein's impact extends to the tumor microenvironment, where it reduces the production of cancer-associated adipocytes (CAAs) and the recruitment of M2d subtype macrophages. In vitro, genistein mitigates the transition of adipocytes into CAAs and curbs inflammatory factors by activating PPAR-γ and degrading nuclear NF-κB. Furthermore, it impedes the acquisition of invasive capabilities and epithelial-mesenchymal transition in breast cancer cells under CAA-induced inflammation, disrupting the Wnt3a/β-catenin pathway. Intriguingly, the PPAR-γ inhibitor T0070907 counteracted genistein's effects in the co-culture system, underscoring the specificity of its action. Our study suggests that genistein could mitigate the adverse effects of obesity on breast cancer by modulating tumor microenvironment. And these findings provide theoretical support for confirming that genistein can be used as a dietary component in the adjuvant treatment of obese breast cancer patients.