Instituto de Biología y Medicina Experimental (IBYME), CONICET, Vuelta de Obligado 2490, C1428ADN, Buenos Aires, Argentina.
Hospital de Agudos Magdalena V de Martínez, General Pacheco, Argentina.
Horm Cancer. 2018 Oct;9(5):338-348. doi: 10.1007/s12672-018-0339-4. Epub 2018 Jun 28.
Endocrine resistance may develop as a consequence of enhanced growth factor signaling. Fibroblast growth factor 2 (FGF2) consists of a low and several high molecular weight forms (HMW-FGF2). We previously demonstrated that antiprogestin-resistant mammary carcinomas display lower levels of progesterone receptor A isoforms (PRA) than B isoforms (PRB). Our aim was to evaluate the role of FGF2 isoforms in breast cancer progression. We evaluated FGF2 expression, cell proliferation, and pathway activation in models with different PRA/PRB ratios. We performed lentiviral infections of different FGF2 isoforms using the human hormone-responsive T47D-YA cells, engineered to only express PRA, and evaluated tumor growth, metastatic dissemination, and endocrine responsiveness. We assessed FGF2 expression and localization in 81 human breast cancer samples. Antiprogestin-resistant experimental mammary carcinomas with low PRA/PRB ratios and T47D-YB cells, which only express PRB, displayed higher levels of HMW-FGF2 than responsive variants. HMW-FGF2 overexpression in T47D-YA cells induced increased tumor growth, lung metastasis, and antiprogestin resistance compared to control tumors. In human breast carcinomas categorized by their PRA/PRB ratio, we found nuclear FGF2 expression in 55.6% of tumor cells. No differences were found between nuclear FGF2 expression and Ki67 proliferation index, tumor stage, or tumor grade. In low-grade tumor samples, moderate to high nuclear FGF2 levels were associated to carcinomas with low PRA/PRB ratio. In conclusion, we show that HMW-FGF2 isoforms are PRB targets which confer endocrine resistance and are localized in the nuclei of breast cancer samples. Hence, targeting intracellular FGF2 may contribute to overcome tumor progression.
内分泌抵抗可能是由于生长因子信号增强而产生的。成纤维细胞生长因子 2（FGF2）由低分子量和几种高分子量形式（HMW-FGF2）组成。我们之前证明，抗孕激素耐药的乳腺癌比孕激素受体 B 型（PRB）表现出较低水平的孕激素受体 A 同工型（PRA）。我们的目的是评估 FGF2 同工型在乳腺癌进展中的作用。我们评估了不同 PRA/PRB 比值模型中的 FGF2 表达、细胞增殖和途径激活。我们使用仅表达 PRA 的人激素反应性 T47D-YA 细胞进行了不同 FGF2 同工型的慢病毒感染，并评估了肿瘤生长、转移扩散和内分泌反应性。我们评估了 81 个人类乳腺癌样本中的 FGF2 表达和定位。低 PRA/PRB 比值的抗孕激素耐药实验性乳腺癌和仅表达 PRB 的 T47D-YB 细胞显示出比反应性变体更高水平的 HMW-FGF2。与对照肿瘤相比，T47D-YA 细胞中 HMW-FGF2 的过表达诱导了肿瘤生长、肺转移和抗孕激素耐药的增加。在根据其 PRA/PRB 比值分类的人类乳腺癌中，我们发现 55.6%的肿瘤细胞存在核 FGF2 表达。核 FGF2 表达与 Ki67 增殖指数、肿瘤分期或肿瘤分级之间未发现差异。在低级别肿瘤样本中，中等至高核 FGF2 水平与低 PRA/PRB 比值的癌相关。总之，我们表明 HMW-FGF2 同工型是 PRB 的靶标，可赋予内分泌抵抗，并定位于乳腺癌样本的核内。因此，靶向细胞内 FGF2 可能有助于克服肿瘤进展。
