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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

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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 6

TAZ mediates the tumorigenic effect of GPER, and its expression correlates with GPER in IDCs of the breast.

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TAZ mediates the tumorigenic effect of GPER, and its expression correlat...
(A) GPER promoted cell proliferation through TAZ. TAZ was knocked down in control or GPER-overexpressing ZR-75-30 cells. Cell proliferation was determined. Error bars represent cell numbers ± SD for triplicate experiments. (B) TAZ was required for GPER to promote tumor growth in a xenograft mouse model. Xenografting was performed in female nude mice using the cells described in A. Four weeks after injection, tumors from mice were extracted and photographed. (C) Verteporfin blocked GPER-driven cell proliferation. ZR-75-30 cells were treated with 10 μM verteporfin, and cell proliferation was measured; n = 3. Error bars represent cell numbers ± SD. (D and E) Positive correlation between GPER and TAZ expression in breast IDCs. Images show IHC staining of GPER and TAZ in 2 serial sections of 3 representative tumors. Scale bars: 50 μm. Total TAZ, cytoplasmic TAZ, nuclear TAZ, nuclear/cytoplasmic TAZ ratio, and GPER expression were analyzed by SPSS linear regression, and the standardized coefficient value is shown. (F and G) The 126 subjects were divided into 4 groups on the basis of their tumor GPER expression scores. Data were analyzed by 1-way ANOVA with LSD correction. Horizontal lines represent the median, and the top and bottom of the boxes represent the 75th and 25th percentiles, respectively. Vec, vector.

Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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