GPER in CAFs regulates hypoxia-driven breast cancer invasion in a CTGF-dependent manner

Ren,Juan; Guo,Hui; Wu,Huili; Tian,Tao; Dong,Danfeng; Zhang,Yuelang; Sui,Yanxia; Zhang,Yong; Zhao,Dongli; Wang,Shufeng; Li,Zongfang; Zhang,Xiaozhi; Liu,Rui; Qian,Jianshneg; Wei,Hongxia; Jiang,Wenjun; Liu,Ya; Li,Yi

doi:10.3892/or.2015.3779

GPER in CAFs regulates hypoxia-driven breast cancer invasion in a CTGF-dependent manner

Authors:
- Juan Ren
- Hui Guo
- Huili Wu
- Tao Tian
- Danfeng Dong
- Yuelang Zhang
- Yanxia Sui
- Yong Zhang
- Dongli Zhao
- Shufeng Wang
- Zongfang Li
- Xiaozhi Zhang
- Rui Liu
- Jianshneg Qian
- Hongxia Wei
- Wenjun Jiang
- Ya Liu
- Yi Li
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Affiliations: Cancer Center, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China, Department of Imaging, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China, Department of Pathology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China, Department of Orthopedics, Xi'an Children Hospital, Xi'an, Shaanxi 710061, P.R. China, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China, Medical School, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
Published online on: February 3, 2015 https://doi.org/10.3892/or.2015.3779
Pages: 1929-1937

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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.

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