Cancer Center, Faculty of Health Sciences, University of Macau, Macau, Macau SAR, 999078, China.
Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau, Macau SAR, 999078, China.
Adv Sci (Weinh). 2021 Nov;8(21):e2100974. doi: 10.1002/advs.202100974. Epub 2021 Sep 13.
Fibroblast growth factor receptor 2 (FGFR2) is a membrane-spanning tyrosine kinase that mediates FGF signaling. Various FGFR2 alterations are detected in breast cancer, yet it remains unclear if activation of FGFR2 signaling initiates tumor formation. In an attempt to answer this question, a mouse model berrying an activation mutation of FGFR2 (FGFR2-S252W) in the mammary gland is generated. It is found that FGF/FGFR2 signaling drives the development of triple-negative breast cancer accompanied by epithelial-mesenchymal transition that is regulated by FGFR2-STAT3 signaling. It is demonstrated that FGFR2 suppresses BRCA1 via the ERK-YY1 axis and promotes tumor progression. BRCA1 knockout in the mammary gland of the FGFR2-S252W mice significantly accelerated tumorigenesis. It is also shown that FGFR2 positively regulates PD-L1 and that a combination of FGFR2 inhibition and immune checkpoint blockade kills cancer cells. These data suggest that the mouse models mimic human breast cancers and can be used to identify actionable therapeutic targets.
成纤维细胞生长因子受体 2（FGFR2）是一种跨膜酪氨酸激酶，介导 FGF 信号转导。在乳腺癌中检测到各种 FGFR2 改变，但 FGFR2 信号激活是否引发肿瘤形成尚不清楚。为了回答这个问题，生成了一种在乳腺中带有 FGFR2 激活突变（FGFR2-S252W）的小鼠模型。研究发现，FGF/FGFR2 信号驱动三阴性乳腺癌的发展，并伴有上皮-间充质转化，该转化受 FGFR2-STAT3 信号调节。研究表明，FGFR2 通过 ERK-YY1 轴抑制 BRCA1，并促进肿瘤进展。FGFR2-S252W 小鼠乳腺中的 BRCA1 敲除显著加速了肿瘤发生。研究还表明，FGFR2 正向调节 PD-L1，FGFR2 抑制和免疫检查点阻断的联合作用可杀死癌细胞。这些数据表明，这些小鼠模型模拟了人类乳腺癌，可以用于鉴定可行的治疗靶点。
