Anti-cancer effects of genistein supplementation and moderate-intensity exercise in high-fat diet-induced breast cancer via regulation of inflammation and adipose tissue metabolism in vivo and in vitro

Background: Breast cancer represents a significant global health concern and is influenced by a range of environmental factors. Increased fat intake and physical inactivity contribute to elevated body fat levels and are strongly linked to breast cancer incidence. Genistein (GEN), isoflavone in soy-derived foods, demonstrates anti-estrogenic properties and anti-cancer effects by regulating various mechanisms such as apoptosis. Regular physical activity prevents the progression and development of cancer by releasing various myokine signaling molecules from the muscles. This study aimed to explore the potential anti-cancer effects of combining GEN supplementation with regular moderate-intensity exercise on breast cancer. Methods: Female BALB/c mice aged 5 weeks were divided into five groups and received GEN, moderate-intensity exercise, or a combination of both throughout the experiment. After 8 weeks of treatment, mammary tumor cells were inoculated into mammary fat pads. Anti-cancer effects of these treatments on apoptosis, macrophage polarization, and adipose tissue wasting mechanisms in breast tumors were analyzed. In addition, U937, a human monocytic leukemia cell line, was treated with phorbol-12-myristate-13-acetate and interleukin (IL)-4 to induce an M2 macrophage phenotype and analyzed markers for M2 polarization. Results: Moderate-intensity exercise alone or in conjunction with GEN proved effective in retarding tumor initiation and growth, leading to reduced tumor volume compared to GEN supplementation alone. The combined regimen enhanced the expression of apoptosis markers and augmented the proportion of M1 macrophages while diminishing M2 macrophages. In vitro, treatment with GEN and myokines suppressed markers of M2 macrophage polarization and expression of the JAK1/STAT6 signaling pathway. Furthermore, the study suggested that the combined intervention of GEN supplementation and moderate-intensity exercise prevented adipose tissue wasting by regulating adipogenesis, lipolysis, and systemic inflammation in subcutaneous fat. Conclusions: The potential anti-cancer effects of GEN supplementation and regular moderate-intensity exercise on breast cancer are mediated through the induction of apoptosis and inhibition of macrophage polarization. They also exert a protective effect on adipose tissue wasting.