Deficiency of metabolic regulator FGFR4 delays breast cancer progression through systemic and microenvironmental metabolic alterations

Abstract

BackgroundEndocrine FGF21 and FGF19 target adipocytes and hepatocytes through betaKlotho (KLB) and FGFR tyrosine kinases effecting glucose, lipid and energy metabolism. Both factors alleviate obesity and metabolic abnormalities which are contributing factors to breast tumor progression. Genomic manipulation of hepatic FGFR4 has uncovered roles of endocrine FGF signaling in both metabolic and cellular homeostasis. Here we determined whether systemic and microenvironmental metabolic alterations caused by the FGFR4 deficiency affect tumorigenesis in breast where FGFR4 is negligible. Breast tumors were induced in the bigenic mice with ablation of FGFR4 and overexpression of TGFα that activates Her2 in the ductal and lobular epithelium surrounded by adipocytes. Mammary tumorigenesis and alterations in systemic and breast microenvironmental metabolic parameters and regulatory pathways were analyzed.ResultsAblation of FGFR4 had no effect on cellular homeostasis and Her2 activity of normal breast tissue. However, the absence of FGFR4 reduced TGFα–driven breast tumor incidence and progression and improved host survival. Notable increases in hepatic and serum FGF21, ileal FGF15/19, adiponectin and adipsin, and decreases in systemic Fetuin A, IGF-1, IGFBP-1, RBP4 and TIMP1 were observed. The ablation affected adipogenesis and secretory function of adipocytes as well as lipogenesis, glycolysis and energy homeostasis associated with the functions of mitochondria, ER and peroxisomes in the breast and tumor foci. Treatment with a chemical inhibitor of NAMPT involved in the pathways inhibited the growth and survival of breast tumor cells and tumor-initiating cell-containing spheres. The FGFR4 ablation also caused elevation of inflammatory factors in the breast.ConclusionsAlthough the primary role of FGFR4 in metabolism occurs in hepatocytes, its ablation results in a net inhibitory effect on mammary tumor progression. We suggest that the tumor-delaying effect of FGFR4 deficiency may be in large part due to elevated anti-obesogenic FGF21 that triggers tumor-suppressing signals from both peripheral and breast adipocytes. The predominant changes in metabolic pathways suggested roles of metabolic effects from both peripheral and breast adipocytes on metabolic reprogramming in breast epithelial cells that contribute to the suppression of tumor progression. These results provide new insights into the contribution of systemic and microenvironmental metabolic effects controlled by endocrine FGF signaling to breast carcinogenesis.

Frequent methylation of the KLOTHO gene and overexpression of the FGFR4 receptor in invasive ductal carcinoma of the breast

“…FGFR4 is a potential effector for KL with the latter protein could be required for the regulation of FGFR4-FGF interactions [21,22]. FGFR4 variants have recently been suggested to play a role in carcinogenesis along with observed overexpression of the receptor in several human cancers [23][24][25][26].…”

MitoNEET Deficiency Alleviates Experimental Alcoholic Steatohepatitis in Mice by Stimulating Endocrine Adiponectin-Fgf15 Axis

“…Growing evidences suggest an association and cross-talk between adipocyte-derived adiponectin and ileum Fgf15 in the regulation of hepatic bile acid homeostasis, lipid metabolism, and inflammation (22)(23)(24)(25)(26)(27). For instance, circulating adiponectin and Fgf15 were concomitantly elevated in Fgfr4 knock-out mice leading to improvement in glucose metabolism, insulin sensitivity, and reduction in body weight under high fat diet feeding (22).…”

TRAMP Prostate Tumor Growth Is Slowed by Walnut Diets Through Altered IGF-1 Levels, Energy Pathways, and Cholesterol Metabolism

“…41 Finally, the reduced IGF-1 level noted as well as the gene and metabolic changes found in walnut-and WO-fed animals parallel many of those identified as related to the inhibition of mice breast cancer growth by FGFR4 knockout. 42 In summary, the current study provides additional evidence that the PCa health benefits, which accompany walnut consumption, are associated with walnut-driven changes in IGF-1 and cholesterol-related systems along with energy-related metabolic systems, all of which have been shown to be important in human PCa. The use of walnuts either whole or as oil as the sole fat source at high levels in the diets presents potential issues regarding walnuts in plausible human diets.…”