Estrogen regulates Hippo signaling via GPER in breast cancer
Xin Zhou, … , Qun-Ying Lei, Kun-Liang Guan
Xin Zhou, … , Qun-Ying Lei, Kun-Liang Guan
Published April 20, 2015
Citation Information: J Clin Invest. 2015;125(5):2123-2135. https://doi.org/10.1172/JCI79573.
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Research Article Oncology

Estrogen regulates Hippo signaling via GPER in breast cancer

Abstract

The G protein–coupled estrogen receptor (GPER) mediates both the genomic and nongenomic effects of estrogen and has been implicated in breast cancer development. Here, we compared GPER expression in cancerous tissue and adjacent normal tissue in patients with invasive ductal carcinoma (IDC) of the breast and determined that GPER is highly upregulated in cancerous cells. Additionally, our studies revealed that GPER stimulation activates yes-associated protein 1 (YAP) and transcriptional coactivator with a PDZ-binding domain (TAZ), 2 homologous transcription coactivators and key effectors of the Hippo tumor suppressor pathway, via the Gαq-11, PLCβ/PKC, and Rho/ROCK signaling pathways. TAZ was required for GPER-induced gene transcription, breast cancer cell proliferation and migration, and tumor growth. Moreover, TAZ expression positively correlated with GPER expression in human IDC specimens. Together, our results suggest that the Hippo/YAP/TAZ pathway is a key downstream signaling branch of GPER and plays a critical role in breast tumorigenesis.

Authors

Xin Zhou, Shuyang Wang, Zhen Wang, Xu Feng, Peng Liu, Xian-Bo Lv, Fulong Li, Fa-Xing Yu, Yiping Sun, Haixin Yuan, Hongguang Zhu, Yue Xiong, Qun-Ying Lei, Kun-Liang Guan

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Figure 1

GPER expression is elevated in IDC of the breast.

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GPER expression is elevated in IDC of the breast. (A) IHC detection of G...
(A) IHC detection of GPER expression in a representative breast IDC sample (including both the superficial and deeper areas) and a matched adjacent normal breast tissue. Tissue slices were H&E stained (left). The corresponding contiguous slices were stained for GPER (brown) and DNA (blue). Panels on the right show higher magnification (original magnification, ×400) of the boxed areas in the middle panels. Scale bars: 50 μm. (B and C) GPER expression was elevated in IDC. GPER staining intensity was quantified using the inForm System as described in Methods. Scores of GPER expression (0 = lowest, 3 = highest) from 30-matched pairs of carcinoma tissues and adjacent normal breast epithelium were analyzed by 1-way ANOVA with least-significant-difference (LSD) correction. Black lines within the data points represent the mean value (B). A total of 115 breast cancer tissues were compared with 30 adjacent normal breast epithelial tissues using 1-way ANOVA with LSD correction and are shown as column plots (C). Data are represented as the mean ± SD.