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 5

YAP/TAZ and TEAD mediate the physiological functions of GPER activation in target gene induction and cell migration.

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YAP/TAZ and TEAD mediate the physiological functions of GPER activation ...
(A and B) TAZ was required for GPER to induce target gene expression. ZR-75-30 cells were transiently transfected with control or TAZ siRNAs. Serum-starved cells were treated with 100 nM G1 for 2 hours as indicated. Protein levels of CTGF and the knockdown efficiency of TAZ were determined by immunoblotting. In A, 8% and 12% refer to the acrylamide concentration in SDS-PAGE. mRNA levels of the indicated target genes were measured by quantitative PCR. Data represent the mean ± SD; n = 3. (C) TEADs were indispensable for GPER to induce target gene expression. The experiments were similar to those depicted in A, except TEAD1/3/4 were knocked down by siRNAs. (D) Knockdown of TAZ impaired G1-induced cell migration. ZR-75-30 cells were transiently transfected with the indicated siRNAs and stimulated with G1 or vehicle for 6 hours after serum starvation. Cell migration was determined by Transwell cell migration assay (50,000 cells/well). Cells were stained with crystal violet (left panels) and quantified (right panel). Data represent the mean ± SD; n = 5. Data were analyzed by 1-way ANOVA with LSD correction. *P < 0.05; ****P < 0.0001. Blots shown are representative of at least 3 independent experiments.