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.

Identifying chemopreventive agents for obesity-associated cancers using an efficient, 3D high-throughput transformation assay.

Obesity is associated with ~40% of cancer diagnoses but there are currently no effective preventive strategies, illustrating a need for chemoprevention. We previously demonstrated that fibroblast growth factor 2 (FGF2) from adipose tissue stimulates malignant transformation, as measured by growth in soft agar, the gold-standard in vitro transformation assay. Because the soft agar assay is unsuitable for high throughput screens (HTS), we developed a novel method using 3D growth in ultra-low attachment conditions as an alternative to growth in agar to discover compounds that inhibit transformation. Treating non-tumorigenic, skin epithelial JB6 P+ cells with FGF2 stimulates growth in ultra-low attachment conditions analogous to growth in the soft agar. This transformation HTS identified picropodophyllin, an insulin growth factor 1 receptor (IGF1R) inhibitor, and fluvastatin, an HMG-CoA reductase inhibitor, as potential chemopreventive agents. These compounds were validated for efficacy using two non-tumorigenic cell lines in soft agar. Another IGF1R inhibitor and other statins were also tested and several were able to inhibit growth in soft agar. This novel 3D HTS platform is fast, robust and has the potential to identify agents for obesity-associated cancer prevention.

A role for FGF2 in visceral adiposity-associated mammary epithelial transformation.

Obesity is a leading risk factor for post-menopausal breast cancer, and this is concerning as 40% of cancer diagnoses in 2014 were associated with overweight/obesity. Despite this epidemiological link, the underlying mechanism responsible is unknown. We recently published that visceral adipose tissue (VAT) releases FGF2 and stimulates the transformation of skin epithelial cells. Furthermore, obesity is differentially associated with many epithelial cancers, and this mechanistic link could be translational. As FGF2 and FGFR1 are implicated in breast cancer progression, we hypothesize that VAT-derived FGF2 plays a translational role in promoting adiposity-associated mammary epithelial cell transformation. In this brief report, data suggest that FGF2/FGFR1 signaling is a potential mechanistic link in VAT-stimulated transformation of breast epithelial cells.

A BET Bromodomain Inhibitor Suppresses Adiposity-Associated Malignant Transformation.

Almost half a million of all new cancers have been attributed to obesity and epidemiologic evidence implicates visceral adipose tissue (VAT) and high-fat diets (HFD) in increasing cancer risk. We demonstrated that VAT-derived fibroblast growth factor 2 (FGF2) from mice fed an HFD or obese individuals stimulates the malignant transformation of epithelial cells. Mechanism-based strategies to prevent this VAT-enhanced tumorigenesis have not been explored. Clinical studies have indicated that bromodomain inhibitors have considerable potential as therapeutic agents for cancer by inhibiting the activity of several oncogenes, including c-Myc; however, their chemopreventive activity is unknown. We show herein that mice with visceral adiposity have elevated nuclear c-Myc expression in their epidermis. We hypothesized that the bromodomain inhibitor I-BET-762 (I-BET) would have efficacy in the prevention of malignant transformation by VAT and FGF2. We tested this hypothesis using our novel models of VAT-stimulated transformation in vitro and FGF2- stimulated tumor formation in vivo We found that I-BET significantly attenuates VAT and FGF2-stimulated transformation and inhibits VAT-induced c-Myc protein expression in several skin and breast epithelial cell lines. Moreover, I-BET attenuated tumor growth significantly in FGF2-treated nude mice. Work is ongoing to determine the role of visceral adiposity in c-Myc activity in several tissues and determine the inhibitory effect of I-BET on VAT-promoted tumors in vivoCancer Prev Res; 11(3); 129-42. ©2017 AACRSee related editorial by Berger and Scacheri, p. 125.

Elucidating the role of adipose tissue secreted factors in malignant transformation.

Although there is a growing number of incidences of obesity and obesity-linked cancers, how excess adiposity actually causes cancer has not been fully explained. Our previous study showed that removal of visceral adipose tissue significantly reduced the number of ultraviolet radiation (UVR)-initiated, high-fat diet-promoted skin cancers. This commentary focuses on our recently published study (Chakraborty, et al., 2017) which demonstrated that fibroblast growth factor-2 (FGF2) released from visceral adipose tissue is a key factor in the malignant transformation of epithelial cells. Within this commentary we have provided additional interpretations and new data in support of the role of FGF2 in adiposity-associated tumorigenesis.