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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Acyltransferases
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Adaptor Proteins, Signal Transducing / physiology
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Animals
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism
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Breast Neoplasms / physiopathology*
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Carcinoma, Ductal, Breast / genetics
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Carcinoma, Ductal, Breast / metabolism
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Carcinoma, Ductal, Breast / physiopathology*
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Cell Division
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Cell Movement
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Cell Transformation, Neoplastic
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Estrogens / pharmacology
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Estrogens / physiology*
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Female
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GTP-Binding Protein alpha Subunits, Gq-G11 / antagonists & inhibitors
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GTP-Binding Protein alpha Subunits, Gq-G11 / genetics
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GTP-Binding Protein alpha Subunits, Gq-G11 / physiology
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Gene Expression Regulation, Neoplastic
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Hippo Signaling Pathway
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Humans
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Intracellular Signaling Peptides and Proteins
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Mice
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Mice, Inbred BALB C
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Neoplasm Proteins / physiology*
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Neoplasms, Hormone-Dependent / genetics
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Neoplasms, Hormone-Dependent / metabolism
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Neoplasms, Hormone-Dependent / physiopathology*
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Phospholipase C beta / physiology
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Phosphoproteins / physiology
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Phosphorylation
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Protein Kinase C / physiology
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Protein Processing, Post-Translational
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Protein Serine-Threonine Kinases / analysis
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / metabolism
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Protein Serine-Threonine Kinases / physiology*
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RNA Interference
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Receptors, Estrogen / drug effects
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Receptors, Estrogen / physiology*
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Receptors, G-Protein-Coupled / drug effects
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Receptors, G-Protein-Coupled / physiology*
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Serine-Threonine Kinase 3
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Signal Transduction / physiology*
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Transcription Factors / physiology
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Transcription, Genetic
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Tumor Suppressor Proteins / analysis
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Tumor Suppressor Proteins / physiology*
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YAP-Signaling Proteins
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rho-Associated Kinases / physiology
Substances
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Adaptor Proteins, Signal Transducing
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Estrogens
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GPER1 protein, human
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Intracellular Signaling Peptides and Proteins
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Neoplasm Proteins
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Phosphoproteins
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Receptors, Estrogen
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Receptors, G-Protein-Coupled
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Transcription Factors
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Tumor Suppressor Proteins
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YAP-Signaling Proteins
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YAP1 protein, human
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Acyltransferases
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TAFAZZIN protein, human
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LATS1 protein, human
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STK4 protein, human
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Protein Serine-Threonine Kinases
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ROCK1 protein, human
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STK3 protein, human
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Serine-Threonine Kinase 3
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rho-Associated Kinases
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Protein Kinase C
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PLCB1 protein, human
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Phospholipase C beta
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GTP-Binding Protein alpha Subunits, Gq-G11