Activation of FGFR2 Signaling Suppresses BRCA1 and Drives Triple-Negative Mammary Tumorigenesis That is Sensitive to Immunotherapy,Advanced Science

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Activation of FGFR2 Signaling Suppresses BRCA1 and Drives Triple-Negative Mammary Tumorigenesis That is Sensitive to Immunotherapy
Advanced Science ( IF 14.3 ) Pub Date : 2021-09-13 , DOI: 10.1002/advs.202100974
Josh Haipeng Lei _{1,

2,

3} , Mi-Hye Lee ₄ , Kai Miao _{1,

2,

3} , Zebin Huang ₁ , Zhicheng Yao ₅ , Aiping Zhang _{1,

2} , Jun Xu _{1,

2} , Ming Zhao _{1,

2} , Zenan Huang ₆ , Xin Zhang _{1,

2} , Si Chen _{1,

2} , N G Jiaying ₁ , Yuzhao Feng ₁ , Fuqiang Xing _{1,

2} , Ping Chen _{1,

2} , Heng Sun _{1,

2,

3} , Qiang Chen _{1,

2,

3} , Tingxiu Xiang ₇ , Lin Chen ₈ , Xiaoling Xu _{1,

2,

3} , Chu-Xia Deng _{1,

2,

3}

Affiliation

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.

中文翻译：

FGFR2 信号传导的激活抑制 BRCA1 并驱动对免疫治疗敏感的三阴性乳腺肿瘤发生

成纤维细胞生长因子受体 2 (FGFR2) 是一种介导 FGF 信号传导的跨膜酪氨酸激酶。在乳腺癌中检测到各种 FGFR2 改变，但尚不清楚 FGFR2 信号的激活是否会启动肿瘤形成。为了回答这个问题，我们建立了乳腺中带有 FGFR2 (FGFR2-S252W) 激活突变的小鼠模型。研究发现，FGF/FGFR2 信号传导驱动三阴性乳腺癌的发展，并伴有受 FGFR2-STAT3 信号传导调节的上皮间质转化。研究表明，FGFR2 通过 ERK-YY1 轴抑制 BRCA1，促进肿瘤进展。 FGFR2-S252W 小鼠乳腺中的 BRCA1 敲除显着加速了肿瘤发生。研究还表明，FGFR2 正向调节 PD-L1，并且 FGFR2 抑制和免疫检查点阻断相结合可以杀死癌细胞。这些数据表明，小鼠模型模仿人类乳腺癌，可用于识别可行的治疗靶点。

更新日期：2021-11-04

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