The G protein-coupled estrogen receptor-1, GPER-1, promotes fibrillogenesis via a Shc-dependent pathway resulting in anchorage-independent growth

Hilary T Magruder; Jeffrey A Quinn; Jean E Schwartzbauer; Jonathan Reichner; Allan Huang; Edward J Filardo

doi:10.1007/s12672-014-0195-9

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The G protein-coupled estrogen receptor-1, GPER-1, promotes fibrillogenesis via a Shc-dependent pathway resulting in anchorage-independent growth

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The G protein-coupled estrogen receptor-1, GPER-1, promotes fibrillogenesis via a Shc-dependent pathway resulting in anchorage-independent growth

Hilary T Magruder, Jeffrey A Quinn, Jean E Schwartzbauer, Jonathan Reichner, Allan Huang and Edward J Filardo

Hormones & cancer, Vol.5(6), pp.390-404

12/2014

DOI: 10.1007/s12672-014-0195-9

PMCID: PMC4964789

PMID: 25096985

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Abstract

The G protein-coupled estrogen receptor-1, GPER-1, coordinates fibronectin (FN) matrix assembly and release of heparan-bound epidermal growth factor (HB-EGF). This mechanism of action results in the recruitment of FN-engaged integrin α5β1 to fibrillar adhesions and the formation of integrin α5β1-Shc adaptor protein complexes. Here, we show that GPER-1 stimulation of murine 4 T1 or human SKBR3 breast cancer cells with 17β-estradiol (E2β) promotes the formation of focal adhesions and actin stress fibers and results in increased cellular adhesion and haptotaxis on FN, but not collagen. These actions are also induced by the xenoestrogen, bisphenol A, and the estrogen receptor (ER) antagonist, ICI 182, 780, but not the inactive stereoisomer, 17α-estradiol (E2α). In addition, we show that GPER-1 stimulation of breast cancer cells allows for FN-dependent, anchorage-independent growth and FN fibril formation in "hanging drop" assays, indicating that these GPER-1-mediated actions occur independently of adhesion to solid substrata. Stable expression of Shc mutant Y317F lacking its primary tyrosyl phosphorylation site disrupts E2β-induced focal adhesion and actin stress fiber formation and abolishes E2β-enhanced haptotaxis on FN and anchorage-dependent growth. Collectively, these data demonstrate that E2β action via GPER-1 enhances cellular adhesivity and FN matrix assembly and allows for anchorage-independent growth, cellular events that may allow for cellular survival, and tumor progression.

Estradiol - analogs & derivatives

Receptors, Estrogen - metabolism

Shc Signaling Adaptor Proteins - metabolism

Receptors, G-Protein-Coupled - metabolism

Stress Fibers - drug effects

Humans

Actins - metabolism

Breast Neoplasms - metabolism

Fulvestrant

Phosphorylation - genetics

Female

Cell Growth Processes - genetics

Estradiol - pharmacology

Phenols - pharmacology

Cell Growth Processes - drug effects

Epidermal Growth Factor - metabolism

Signal Transduction - genetics

Cell Adhesion - drug effects

Mutation - genetics

Estrogen Receptor Modulators - pharmacology

Fibronectins - metabolism

Animals

Shc Signaling Adaptor Proteins - genetics

Signal Transduction - drug effects

Focal Adhesions - metabolism

Cell Line, Tumor

Benzhydryl Compounds - pharmacology

Mice

Details

Title: Subtitle: The G protein-coupled estrogen receptor-1, GPER-1, promotes fibrillogenesis via a Shc-dependent pathway resulting in anchorage-independent growth
Creators: Hilary T Magruder - Division of Hematology and Oncology, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, 02903, USA
Jeffrey A Quinn
Jean E Schwartzbauer
Jonathan Reichner
Allan Huang
Edward J Filardo
Resource Type: Journal article
Publication Details: Hormones & cancer, Vol.5(6), pp.390-404
Publisher: United States
DOI: 10.1007/s12672-014-0195-9
PMID: 25096985
PMCID: PMC4964789
ISSN: 1868-8497
eISSN: 1868-8500
Grant note: R01 CA160611 / NCI NIH HHS CA119165-01A2 / NCI NIH HHS R01 CA119165 / NCI NIH HHS
Language: English
Date published: 12/2014
Academic Unit: Pharmaceutical Sciences and Experimental Therapeutics; Surgery; Internal Medicine
Record Identifier: 9984051728102771

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