Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USA.
Department of Pediatrics and Human Development, Michigan State University, Grand Rapids, MI 49503, USA.
Cells. 2020 Oct 1;9(10):2224. doi: 10.3390/cells9102224.
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.
肥胖与乳腺癌风险增加和癌症预后较差有关；然而，这些观察结果的确切病因尚未完全确定。我们之前的研究表明，脂肪组织衍生的成纤维细胞生长因子 2（FGF2）通过激活成纤维细胞生长因子受体 1（FGFR1）促进上皮细胞的恶性转化。肥胖时 FGF2 增加，血清水平升高与内分泌抵抗性乳腺癌有关。瘦素是肥胖的标志物，通过多种机制促进乳腺癌的发生。在这项研究中，我们利用公共基因表达数据集来评估乳腺癌中 FGFR1、瘦素和瘦素受体（LepR）之间的关联。我们显示原发性乳腺癌中 FGFR1 与瘦素蛋白拷贝数呈正相关。这些观察结果与 Janus 激酶 2（Jak2）mRNA 与瘦素受体（LepR）mRNA 和 FGFR1mRNA 之间的正相关一致。此外，两种单独的 Jak2 抑制剂均可减弱瘦素+FGF2 刺激和小鼠脂肪组织刺激 MCF-10A 转化。这些结果表明，肥胖患者血清中升高的 FGF2 和瘦素如何通过 Jak2 信号促进表达升高的 FGFR1 和 LepR 的肿瘤中的癌症进展。因此，Jak2 是 FGFR1 扩增型乳腺癌的潜在治疗靶点，尤其是在肥胖的情况下。
