GPER-mediated proliferation and estradiol production in breast cancer-associated fibroblasts.
Cancer-associated fibroblasts (CAFs) are crucial co-mediators of breast cancer progression. Estrogen is the predominant driving force in the cyclic regulation of the mammary extracellular matrix, thus potentially affecting the tumor-associated stroma. Recently, a third estrogen receptor, estrogen (G-protein-coupled) receptor (GPER), has been reported to be expressed in breast CAFs. In this study, GPER was detected by immunohistochemical analysis in stromal fibroblasts of 41.8% (59/141) of the primary breast cancer samples. GPER expression in CAFs isolated from primary breast cancer tissues was confirmed by immunostaining and RT-PCR analyses. Tamoxifen (TAM) in addition to 17β-estradiol (E₂) and the GPER agonist G1 activated GPER, resulting in transient increases in cell index, intracellular calcium, and ERK1/2 phosphorylation. Furthermore, TAM, E₂, and G1 promoted CAF proliferation and cell-cycle progression, both of which were blocked by GPER interference, the selective GPER antagonist G15, the epidermal growth factor receptor (EGFR) inhibitor AG1478, and the ERK1/2 inhibitor U0126. Importantly, TAM as well as G1 increased E₂ production in breast CAFs via GPER/EGFR/ERK signaling when the substrate of E₂, testosterone, was added to the medium. GPER-induced aromatase upregulation was probably responsible for this phenomenon, as TAM- and G1-induced CYP19A1 gene expression was reduced by GPER knockdown and G15, AG1478, and U0126 administration. Accordingly, GPER-mediated CAF-dependent estrogenic effects on the tumor-associated stroma are conceivable, and CAF is likely to contribute to breast cancer progression, especially TAM resistance, via a positive feedback loop involving GPER/EGFR/ERK signaling and E₂ production.
Department of Breast and Thyroid Surgery, the Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China Department of Endocrine and Breast Surgery, the First Affiliated Hospital of Chongqing Medical University, No. 1 You-Yi Road, Yu-zhong District, Chongqing 400016, China Department of Gynecology and Obstetrics, Chongqing Health Center for Women and Children, Chongqing 400010, China Key Laboratory of Laboratory Medical Diagnostics, Chinese Ministry of Education, Chongqing Medical University, No. 1 Yi-Xue-Yuan Road, Yu-zhong District, Chongqing 400016, China.
Haojun
H
Luo
Guanglun
G
Yang
Tenghua
T
Yu
Shujuan
S
Luo
Chengyi
C
Wu
Yan
Y
Sun
Manran
M
Liu
Gang
G
Tu
D001943:Breast Neoplasms / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003517:Cyclopentanes / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D011804:Quinolines / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000819:agonists / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000378:metabolism*; D013629:Tamoxifen / Q000494:pharmacology
C517943:1-(4-(6-bromobenzo(1,3)dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta(c)quinolin-8-yl)ethanone; D003517:Cyclopentanes; C109584:GPER1 protein, human; D011804:Quinolines; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D013629:Tamoxifen; D004958:Estradiol
CAF; GPER; breast cancer; tamoxifen resistance