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Activation of FGFR2 Signaling Suppresses BRCA1 and Drives Triple-Negative Mammary Tumorigenesis That is Sensitive to Immunotherapy
Lei, Josh Haipeng1,2,3; Lee, Mi Hye4; Miao, Kai1,2,3; Huang, Zebin1; Yao, Zhicheng5; Zhang, Aiping1,2; Xu, Jun1,2; Zhao, Ming1,2; Huang, Zenan6; Zhang, Xin1,2; Chen, Si1,2; Jiaying, N. G.1; Feng, Yuzhao1; Xing, Fuqiang1,2; Chen, Ping1,2; Sun, Heng1,2,3; Chen, Qiang1,2,3; Xiang, Tingxiu7; Chen, Lin8; Xu, Xiaoling1,2,3; Deng, Chu Xia1,2,3
2021-11-01
Source PublicationAdvanced Science
ISSN2198-3844
Volume8Issue:21
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.

KeywordBrca1 Breast Cancer Fgfr2 Inhibitor Fgfr2-s252w Tumor Slice Culture
DOI10.1002/advs.202100974
URLView the original
Indexed BySCIE
Language英語English
WOS Research AreaComputer Science ; Science & Technology - Other Topics ; Materials Science
WOS SubjectChemistry, Multidisciplinary ; Nanoscience & Nanotechnology ; Materials Science, Multidisciplinary
WOS IDWOS:000695125400001
Scopus ID2-s2.0-85114727211
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Document TypeJournal article
CollectionUniversity of Macau
Corresponding AuthorDeng, Chu Xia
Affiliation1.Cancer Center, Faculty of Health Sciences, University of Macau, 999078, Macao
2.Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, 999078, Macao
3.MOE Frontier Science Centre for Precision Oncology, University of Macau, Taipa, 999078, Macao
4.Department of Oncology, Georgetown-Lombardi Comprehensive Cancer Center, Georgetown University, Washington, 20057, United States
5.Department of General Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510000, China
6.Department of Thyroid and Breast Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510000, China
7.Oncology Laboratory, The First Affiliated hospital of Chongqing Medical University, Chongqing, 400016, China
8.Center of Bone Metabolism and Repair, Department of Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, 400038, China
First Author AffilicationCancer Centre;  Faculty of Health Sciences;  University of Macau
Corresponding Author AffilicationCancer Centre;  Faculty of Health Sciences;  University of Macau
Recommended Citation
GB/T 7714
Lei, Josh Haipeng,Lee, Mi Hye,Miao, Kai,et al. Activation of FGFR2 Signaling Suppresses BRCA1 and Drives Triple-Negative Mammary Tumorigenesis That is Sensitive to Immunotherapy[J]. Advanced Science,2021,8(21).
APA Lei, Josh Haipeng.,Lee, Mi Hye.,Miao, Kai.,Huang, Zebin.,Yao, Zhicheng.,Zhang, Aiping.,Xu, Jun.,Zhao, Ming.,Huang, Zenan.,Zhang, Xin.,Chen, Si.,Jiaying, N. G..,Feng, Yuzhao.,Xing, Fuqiang.,Chen, Ping.,Sun, Heng.,Chen, Qiang.,Xiang, Tingxiu.,Chen, Lin.,...&Deng, Chu Xia.(2021).Activation of FGFR2 Signaling Suppresses BRCA1 and Drives Triple-Negative Mammary Tumorigenesis That is Sensitive to Immunotherapy.Advanced Science,8(21).
MLA Lei, Josh Haipeng,et al."Activation of FGFR2 Signaling Suppresses BRCA1 and Drives Triple-Negative Mammary Tumorigenesis That is Sensitive to Immunotherapy".Advanced Science 8.21(2021).
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