2. Academic Validation
  3. Progesterone activates GPR126 to promote breast cancer development via the Gi pathway

Progesterone activates GPR126 to promote breast cancer development via the Gi pathway

  • Proc Natl Acad Sci U S A. 2022 Apr 12;119(15):e2117004119. doi: 10.1073/pnas.2117004119.
Wentao An 1,  Hui Lin 1,  Lijuan Ma 2,  Chao Zhang 2,  Yuan Zheng 3,  Qiuxia Cheng 1,  Chuanshun Ma 4,  Xiang Wu 2,  Zihao Zhang 1,  Yani Zhong 2,  Menghui Wang 1,  Dongfang He 2,  Zhao Yang 2,  Lutao Du 5,  Shiqing Feng 6 7 8,  Chuanxin Wang 5,  Fan Yang 1 6,  Peng Xiao 2 5,  Pengju Zhang 2,  Xiao Yu 1 2,  Jin-Peng Sun 2 3 5 6
Affiliations

Affiliations

  • 1 Key Laboratory Experimental Teratology of the Ministry of Education, Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.
  • 2 Key Laboratory Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.
  • 3 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, China.
  • 4 School of Pharmacy, Binzhou Medical University, Yantai 264003, China.
  • 5 Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250033, China.
  • 6 Advanced Medical Research Institute, Shandong University, Jinan 250012, China.
  • 7 Department of Orthopaedics, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.
  • 8 Shandong University Center for Orthopaedics, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.
PMID: 35394864 DOI: 10.1073/pnas.2117004119
Abstract

GPR126 is a member of the adhesion G protein-coupled receptors (aGPCRs) that is essential for the normal development of diverse tissues, and its mutations are implicated in various pathological processes. Here, through screening 34 steroid Hormones and their derivatives for cAMP production, we found that progesterone (P4) and 17-hydroxyprogesterone (17OHP) could specifically activate GPR126 and trigger its downstream Gi signaling by binding to the ligand pocket in the seven-transmembrane domain of the C-terminal fragment of GPR126. A detailed mutagenesis screening according to a computational simulated structure model indicated that K1001ECL2 and F1012ECL2 are key residues that specifically recognize 17OHP but not progesterone. Finally, functional analysis revealed that progesterone-triggered GPR126 activation promoted cell growth in vitro and tumorigenesis in vivo, which involved Gi-SRC pathways in a triple-negative breast Cancer model. Collectively, our work identified a membrane receptor for progesterone/17OHP and delineated the mechanisms by which GPR126 participated in potential tumor progression in triple-negative breast Cancer, which will enrich our understanding of the functions and working mechanisms of both the aGPCR member GPR126 and the steroid hormone progesterone.

Keywords

17OHP; GPR126; Gi; TNBC; progesterone.

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