FGF1 supports glycolytic metabolism through the estrogen receptor in endocrine-resistant and obesity-associated breast cancer.
FGF1 supports glycolytic metabolism through the estrogen receptor in endocrine-resistant and obesity-associated breast cancer.
复制标题
DOI：
10.1186/s13058-023-01699-0
复制
发表时间：
2023-08-22
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
肥胖增加乳腺癌风险和乳腺癌特异性死亡率，特别是对于雌激素受体（ER）阳性肿瘤患者。身体质量指数（BMI）用于定义肥胖，但它可能不是个体水平上乳腺癌风险或预后的最佳预测因子。成人体重增加是乳腺癌风险的独立指标。我们先前的工作描述了肥胖、ER阳性乳腺癌和体重增加的小鼠模型，并确定成纤维细胞生长因子受体（FGFR）是肿瘤进展的潜在驱动因素。在脂肪组织扩张过程中，肥大脂肪细胞产生FGF 1配体作为基质前脂肪细胞的刺激物，基质前脂肪细胞增殖和分化以提供额外的脂质储存能力。在乳腺脂肪组织中，FGF 1的产生可能刺激癌细胞增殖和肿瘤进展。我们探讨了FGF 1对ER阳性内分泌敏感型和耐药型乳腺癌的影响，并将其与经典的ER配体雌二醇的影响进行了比较。我们使用了非靶向蛋白质组学、特异性免疫印迹分析、基因表达谱分析和乳腺癌细胞的功能代谢评估。这些结果在肥胖小鼠的肿瘤和肥胖女性的乳腺癌数据集中得到了验证。在雌激素剥夺治疗后的肥胖雌性小鼠中生长的细胞中，FGF 1独立于雌二醇刺激ER磷酸化。对内分泌敏感和耐药乳腺癌细胞的磷酸化和总蛋白质组、基因组和功能分析表明，FGF 1促进了以糖酵解代谢为特征的细胞表型。在内分泌敏感但不耐内分泌的乳腺癌细胞中，线粒体代谢也受到FGF 1的调节。基因表达谱的比较表明，肥胖妇女的肿瘤与内分泌抵抗性乳腺癌细胞有共同的特征。总的来说，我们的数据表明，肥胖和体重增加促进乳腺癌进展的一种机制是通过雌激素非依赖性ER激活和癌细胞代谢重编程，部分由FGF/FGFR驱动。许多ER阳性乳腺癌患者的一线治疗是使用芳香化酶抑制剂抑制雌激素合成。在体重增加的肥胖女性中，局部产生的FGF 1可能会激活ER，促进癌细胞代谢重编程和肿瘤进展，而不依赖于雌激素。在线版本包含补充材料，可通过10.1186/s13058-023-01699-0获得。
Obesity increases breast cancer risk and breast cancer-specific mortality, particularly for people with estrogen receptor (ER)-positive tumors. Body mass index (BMI) is used to define obesity, but it may not be the best predictor of breast cancer risk or prognosis on an individual level. Adult weight gain is an independent indicator of breast cancer risk. Our previous work described a murine model of obesity, ER-positive breast cancer, and weight gain and identified fibroblast growth factor receptor (FGFR) as a potential driver of tumor progression. During adipose tissue expansion, the FGF1 ligand is produced by hypertrophic adipocytes as a stimulus to stromal preadipocytes that proliferate and differentiate to provide additional lipid storage capacity. In breast adipose tissue, FGF1 production may stimulate cancer cell proliferation and tumor progression. We explored the effects of FGF1 on ER-positive endocrine-sensitive and resistant breast cancer and compared that to the effects of the canonical ER ligand, estradiol. We used untargeted proteomics, specific immunoblot assays, gene expression profiling, and functional metabolic assessments of breast cancer cells. The results were validated in tumors from obese mice and breast cancer datasets from women with obesity. FGF1 stimulated ER phosphorylation independently of estradiol in cells that grow in obese female mice after estrogen deprivation treatment. Phospho- and total proteomic, genomic, and functional analyses of endocrine-sensitive and resistant breast cancer cells show that FGF1 promoted a cellular phenotype characterized by glycolytic metabolism. In endocrine-sensitive but not endocrine-resistant breast cancer cells, mitochondrial metabolism was also regulated by FGF1. Comparison of gene expression profiles indicated that tumors from women with obesity shared hallmarks with endocrine-resistant breast cancer cells. Collectively, our data suggest that one mechanism by which obesity and weight gain promote breast cancer progression is through estrogen-independent ER activation and cancer cell metabolic reprogramming, partly driven by FGF/FGFR. The first-line treatment for many patients with ER-positive breast cancer is inhibition of estrogen synthesis using aromatase inhibitors. In women with obesity who are experiencing weight gain, locally produced FGF1 may activate ER to promote cancer cell metabolic reprogramming and tumor progression independently of estrogen. The online version contains supplementary material available at 10.1186/s13058-023-01699-0.
登录
查看更多内容
影响因子：
5.8
作者：
Gu, Zuguang;Eils, Roland;Schlesner, Matthias
通讯作者：
Schlesner, Matthias
影响因子：
3.8
作者：
Bergman, Riley;Berko, Yvonne A.;Rexer, Brent N.
通讯作者：
Rexer, Brent N.
影响因子：
45.3
作者：
Folkerd, Elizabeth J.;Dixon, J. Michael;Dowsett, Mitch
通讯作者：
Dowsett, Mitch
DOI：
10.1158/1078-0432.ccr-17-1232
发表时间：
2017-10-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Formisano L;Stauffer KM;Young CD;Bhola NE;Guerrero-Zotano AL;Jansen VM;Estrada MM;Hutchinson KE;Giltnane JM;Schwarz LJ;Lu Y;Balko JM;Deas O;Cairo S;Judde JG;Mayer IA;Sanders M;Dugger TC;Bianco R;Stricker T;Arteaga CL
通讯作者：
Arteaga CL
影响因子：
3.8
作者：
Creighton, Chad J.;Sada, Yvonne H.;Chang, Jenny C.
通讯作者：
Chang, Jenny C.