Non-alcoholic fatty liver disease promotes breast cancer progression through upregulated hepatic fibroblast growth factor 21

Abstract

Breast cancer is, so far, the most commonly diagnosed cancer worldwide. High-fat diet-induced metabolic diseases are the major controllable risk factor for the incidence and progression of breast cancer, of which non-alcoholic fatty liver disease (NAFLD), the most prevalent liver disorder globally, is greatly common in patients with high-fat diets and has been found that contribute to the high incidence and poor prognosis of breast cancer. However, the role of NAFLD in breast cancer has long been underestimated, and the mechanism is far from clear. The liver is a gland with secretory functions. Plenty of substances, including bioactive proteins, are produced or metabolized in the liver and reach the body through the circulation system, realizing the extrahepatic functions. Here, the secretory dysfunction of the liver under NAFLD was considered the potential mechanism contributing to breast cancer progression. With high-fat diet intervention, it was found promoted breast cancer tumor growth and cell viability in both in vivo and in vitro models with typical NAFLD characteristics. The secretory profile of the NAFLD liver was explored, and fibroblast growth factor 21 (FGF21) stood out as significantly overexpressed in NAFLD. As a hepatokine, circulating FGF21 exclusively from the liver, which was consistently upregulated in the models we established. Both peritumoral and systemic FGF21 administration within 4 weeks facilitated tumor growth in the E0771 allograft breast cancer model, whereas FGF21 knockout diminished the high-fat-diet-induced mammary tumor growth and resulted in comparable tumor condition, highlighting the significance of FGF21 overexpression in the tumor-promoting effects of NAFLD on breast cancer. Mechanically, FGF21 receptors FGFR1, FGFR2, FGFR3, FGFR4, and co-receptor β-klotho were generally expressed in all breast cancer cell lines tested, including MDA-MB-231, BT-549, MCF-7, and E0771. Exogenous FGF21 treatment enhanced the cell viability and anti-apoptotic ability of breast cancer cells via STAT3 and Akt/FoXO1/Bcl-2 signaling pathways. Furthermore, FGF21 had antagonistic interactions with chemotherapy doxorubicin in breast cancer, as shown by increased cell viability, mitigated cell apoptosis and caspase activation, and improved mitochondrial membrane condition and cytochrome c stabilization in doxorubicin-treated cancer cells with additional FGF21 administration. Besides, the expression pattern of FGF21 in breast tumor tissues has not been reported yet. Here, in samples from patients with different molecular types of breast cancer, it was found that breast tumor tissues significantly overexpressed FGF21 compared to paired normal tissues regardless of the molecular type. And patients with high intratumoral FGF21 levels showed shorter overall survival time and disease-free survival, lower survival rates, and higher recurrence rates. Taken together, findings in this research support a new role of FGF21 as a mediator upregulated in the NAFLD context that promotes breast cancer development, serving as a promising cancer therapeutic target. More importantly, it uncovered a distant liver-breast cancer crosstalk, which is not only a new avenue for exploring the breast cancer mechanism, but also a support for the Traditional Chinese Medicine concepts that “liver being innate basis of women” and “treating breast disease from the liver”.