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

Wyatt Boothby-Shoemaker,Bin Chen,Jamie J Bernard,Rama Shankar,Shreya Paithankar,Vanessa Benham

doi:10.3390/cells9102224

Wyatt Boothby-Shoemaker, Bin Chen + Show 4 more

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https://doi.org/10.3390/cells9102224

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Journal: Cells	Publication Date: Oct 1, 2020
Citations: 13	License type: CC BY 4.0

Affiliation: Michigan State University

Abstract

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.

Highlights

Obesity, as defined by the body mass index (BMI) > 30 kg/m2, is increasing globally and contributes to both cancer risk and mortality worldwide representing an enormous cost to public health [1,2,3,4,5].One hundred million children and adolescents and 600 million adults are currently obese [1,2] and constitute an at-risk segment of the population for developing obesity-linked malignancies, such as breast cancer
Our bioinformatics results analyze publicly available genomic data to describe the expression of fibroblast growth factor receptor-1 (FGFR1) and leptin in breast tumors
While the studies do not fully elucidate these complexities, they provide relationship data on two receptors in breast tumors that may be influenced by excess adipose tissue and drive tumor progression, leptin receptor (LepR) and FGFR1

Summary

Introduction

One hundred million children and adolescents and 600 million adults are currently obese [1,2] and constitute an at-risk segment of the population for developing obesity-linked malignancies, such as breast cancer. An elevated BMI is associated primarily with postmenopausal, estrogen receptor (ER)-positive (ER+ ) breast cancer; in pre-menopausal women, obesity is associated with a lower risk of ER+ breast cancer and a higher risk of triple negative breast cancer (TNBC) [6,7,8,9,10,11]. Central/visceral obesity, which reflects the accumulation of a harmful type of adipose tissue, visceral adipose tissue (VAT), is a strong predictor of premenopausal TNBC [6,9]. The molecular mechanisms underlying breast cancer risk with both general/overall and central/visceral adiposity are complex and have not been fully elucidated.

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