Tremella fuciformis polysaccharide suppresses breast cancer by improving hyperinsulinemia via SIRT3 in postmenopausal mice with obesity

Obesity and its associated metabolic disturbances enhance the risk and progression of a variety of tumors, including human postmenopausal breast cancer. Polysaccharide interventions such as Tremella fuciformis polysaccharide (TFP) can alleviate the metabolic dysfunctions caused by obesity and inhibit tumor growth. In the present study, we endeavored to explore the regulatory effects of TFP on high-fat diet (HFD)-induced obese mice with postmenopausal breast cancer. We initially discovered that TFP could significantly mitigate HFD-induced metabolic dysfunction in mice, as demonstrated by the improved glucose tolerance and insulin resistance (IR), reduced hepatic lipid deposition, and ameliorated histological changes in mammary fat pads. Subsequently, TFP administration restricted HFD-facilitated mammary tumor growth in Py230 orthotopic mouse models. Moreover, TFP potently suppressed pre-existing mammary tumor growth in postmenopausal mouse models fed with HFD, along with alleviated metabolic disorders. Notably, in vitro studies indicated that insulin exposure stimulated murine breast cancer cell proliferation and migration, while being significantly inhibited by TFP co-culture. Animal studies confirmed that hyperinsulinemia drove breast cancer progression, but could be suppressed in HFD-fed postmenopausal mice upon TFP administration. TFP additionally constrains local tumor recurrence in HFD-fed postmenopausal mice with improved lung metastasis. Bioinformatic, molecular docking, and molecular biology analyses suggested that TFP could target sirtuin 3 (SIRT3) and elevate SIRT3 expression levels in breast cancer cells, accompanied by decreased expression of its downstream signals, including phosphorylated mammalian target of rapamycin (p-mTOR), p-S6 kinase (S6K), and hypoxia-inducible factor (HIF)-1α. Similarly, TFP also up-regulates SIRT3 expression levels in the liver, mammary fat pad, and tumor tissues of postmenopausal mice with HFD-induced obesity. Significantly, the inhibitory effects of TFP on breast cancer cell proliferation and migration stimulated by insulin were completely abolished when SIRT3 expression was deleted, elucidating that enhancing SIRT3 expression might be requisite for TFP to exert its anti-tumor role against breast cancer under hyperinsulinemia. Our findings demonstrated that TFP consumption is likely to be efficacious in the prevention and treatment of obesity-associated breast cancer mainly through modulating SIRT3 signaling.