title: GPER in CAFs regulates hypoxia-driven breast cancer invasion in a CTGF-dependent manner.
abstract: Recent advances indicate that cancer‑associated fibroblasts (CAFs) play a key role in cancer progression by contributing to invasion, metastasis and angiogenesis. Solid tumors often experience low oxygen tension environments, which induce gene expression changes and biological features leading to poor outcomes. The G-protein estrogen receptor (GPER) exhibits a stimulatory role in diverse types of cancer cells and in CAFs under hypoxic conditions. We investigated the role of CAFs and hypoxia in breast cancer aggressiveness, and examined the effect of GPER in CAFs on hypoxia-driven breast cancer progression. The results showed that hypoxia upregulated HIF-1α, GPER and α-SMA expression in CAFs, and induced the secretion of Interleukin-6 (IL-6), vascular endothelial growth factor (VEGF) and connective tissue growth factor (CTGF) in CAFs. However, GPER silencing abrogated the above hypoxia-driven cytokine expression in CAFs. Moreover, knockdown of GPER in CAFs suppressed breast cancer cell invasion induced by CAF conditioned media (CM). Furthermore, GPER silencing in CAFs inhibited hypoxia-increased CTGF expression in CAFs and breast cancer cells cultured with CM from CAFs under hypoxic conditions. In addition, CTGF is responsible for the observed effects of GPER on CAFs activation and breast cancer invasion. Our findings further extend the molecular mechanisms through which the tumor microenvironment may contribute to cancer progression.
authors: Cancer Center, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors: Juan
authors: J
authors: Ren
authors: Cancer Center, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors: Hui
authors: H
authors: Guo
authors: Cancer Center, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors: Huili
authors: H
authors: Wu
authors: Cancer Center, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors: Tao
authors: T
authors: Tian
authors: Cancer Center, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors: Danfeng
authors: D
authors: Dong
authors: Department of Imaging, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors: Yuelang
authors: Y
authors: Zhang
authors: Department of Pathology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors: Yanxia
authors: Y
authors: Sui
authors: Department of Orthopedics, Xi'an Children Hospital, Xi'an, Shaanxi 710061, P.R. China.
authors: Yong
authors: Y
authors: Zhang
authors: Cancer Center, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors: Dongli
authors: D
authors: Zhao
authors: Cancer Center, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors: Shufeng
authors: S
authors: Wang
authors: Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors: Zongfang
authors: Z
authors: Li
authors: Cancer Center, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors: Xiaozhi
authors: X
authors: Zhang
authors: Cancer Center, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors: Rui
authors: R
authors: Liu
authors: Cancer Center, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors: Jianshneg
authors: J
authors: Qian
authors: Cancer Center, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors: Hongxia
authors: H
authors: Wei
authors: Medical School, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors: Wenjun
authors: W
authors: Jiang
authors: Cancer Center, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors: Ya
authors: Y
authors: Liu
authors: Cancer Center, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
authors: Yi
authors: Y
authors: Li
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D015687:Cell Hypoxia / Q000502:physiology*; D002460:Cell Line; D055513:Connective Tissue Growth Factor / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000502:physiology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D017154:Stromal Cells / Q000502:physiology; D059016:Tumor Microenvironment
chemical_list: C526317:CCN2 protein, human; D017077:Culture Media, Conditioned; D016207:Cytokines; C109584:GPER1 protein, human; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D055513:Connective Tissue Growth Factor