Open AccessActivation of FGFR2 Signaling Suppresses BRCA1 and Drives Triple‐Negative Mammary Tumorigenesis That is Sensitive to Immunotherapy
Author(s) -
Lei Josh Haipeng,
Lee MiHye,
Miao Kai,
Huang Zebin,
Yao Zhicheng,
Zhang Aiping,
Xu Jun,
Zhao Ming,
Huang Zenan,
Zhang Xin,
Chen Si,
Jiaying NG,
Feng Yuzhao,
Xing Fuqiang,
Chen Ping,
Sun Heng,
Chen Qiang,
Xiang Tingxiu,
Chen Lin,
Xu Xiaoling,
Deng ChuXia
Publication year - 2021
Publication title -
advanced science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.388
H-Index - 100
ISSN - 2198-3844
DOI - 10.1002/advs.202100974
Subject(s) - cancer research , fibroblast growth factor receptor 2 , carcinogenesis , triple negative breast cancer , fibroblast growth factor , signal transduction , receptor tyrosine kinase , mammary tumor , mapk/erk pathway , tumor progression , fibroblast growth factor receptor 1 , cancer , biology , breast cancer , chemistry , microbiology and biotechnology , medicine , receptor , biochemistry
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.