The Relationship between Leptin, the Leptin Receptor and FGFR1 in Primary Human Breast Tumors

Obesity is associated with increased breast cancer risk and poorer cancer outcomes; however, the precise etiology of these observations has not been fully identified. Our previous research suggests that adipose tissue-derived fibroblast growth factor-2 (FGF2) promotes the malignant transformation of epithelial cells through the activation of fibroblast growth factor receptor-1 (FGFR1). FGF2 is increased in the context of obesity, and increased sera levels have been associated with endocrine-resistant breast cancer. Leptin is a marker of obesity and promotes breast carcinogenesis through several mechanisms. In this study, we leverage public gene expression datasets to evaluate the associations between FGFR1, leptin, and the leptin receptor (LepR) in breast cancer. We show a positive association between FGFR1 and leptin protein copy number in primary breast tumors. These observations coincided with a positive association between Janus kinase 2 (Jak2) mRNA with both leptin receptor (LepR) mRNA and FGFR1 mRNA. Moreover, two separate Jak2 inhibitors attenuated both leptin+FGF2-stimulated and mouse adipose tissue-stimulated MCF-10A transformation. These results demonstrate how elevated sera FGF2 and leptin in obese patients may promote cancer progression in tumors that express elevated FGFR1 and LepR through Jak2 signaling. Therefore, Jak2 is a potential therapeutic target for FGFR1 amplified breast cancer, especially in the context of obesity.