Activation of FGFR2 Signaling Suppresses BRCA1 and Drives Triple‐Negative Mammary Tumorigenesis That is Sensitive to Immunotherapy
Open Access
- 13 September 2021
- journal article
- research article
- Published by Wiley in Advanced Science
- Vol. 8 (21)
- https://doi.org/10.1002/advs.202100974
Abstract
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.Keywords
Funding Information
- Universidade de Macau (CPG2021‐00021‐FHS, MYRG2017‐00113‐FHS)
- National Natural Science Foundation of China (NSFC‐82030094)
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