The antitumorigenic function of EGFR in metastatic breast cancer is regulated by expression of Mig6

Michael K Wendt; Whitney K Williams; Pete E Pascuzzi; Nikolas G Balanis; Barbara J Schiemann; Cathleen R Carlin; William P Schiemann

doi:10.1016/j.neo.2014.11.009

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The antitumorigenic function of EGFR in metastatic breast cancer is regulated by expression of Mig6

Journal article

Open access

Peer reviewed

The antitumorigenic function of EGFR in metastatic breast cancer is regulated by expression of Mig6

Michael K Wendt, Whitney K Williams, Pete E Pascuzzi, Nikolas G Balanis, Barbara J Schiemann, Cathleen R Carlin and William P Schiemann

Neoplasia (New York, N.Y.), Vol.17(1), pp.124-133

01/01/2015

DOI: 10.1016/j.neo.2014.11.009

PMCID: PMC4309683

PMID: 25622905

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Abstract

Numerous studies by our lab and others demonstrate that epidermal growth factor receptor (EGFR) plays critical roles in primary breast cancer (BC) initiation, growth and dissemination. However, clinical trials targeting EGFR function in BC have lead to disappointing results. In the current study we sought to identify the mechanisms responsible for this disparity by investigating the function of EGFR across the continuum of the metastatic cascade. We previously established that overexpression of EGFR is sufficient for formation of in situ primary tumors by otherwise nontransformed murine mammary gland cells. Induction of epithelial-mesenchymal transition (EMT) is sufficient to drive the metastasis of these EGFR-transformed tumors. Examining growth factor receptor expression across this and other models revealed a potent downregulation of EGFR through metastatic progression. Consistent with diminution of EGFR following EMT and metastasis EGF stimulation changes from a proliferative to an apoptotic response in in situ versus metastatic tumor cells, respectively. Furthermore, overexpression of EGFR in metastatic MDA-MB-231 BC cells promoted their antitumorigenic response to EGF in three dimensional (3D) metastatic outgrowth assays. In line with the paradoxical function of EGFR through EMT and metastasis we demonstrate that the EGFR inhibitory molecule, Mitogen Induced Gene-6 (Mig6), is tumor suppressive in in situ tumor cells. However, Mig6 expression is absolutely required for prevention of apoptosis and ultimate metastasis of MDA-MB-231 cells. Further understanding of the paradoxical function of EGFR between primary and metastatic tumors will be essential for application of its targeted molecular therapies in BC.

Adaptor Proteins, Signal Transducing - genetics

Animals

Breast Neoplasms - genetics

Breast Neoplasms - metabolism

Breast Neoplasms - pathology

Cell Line, Tumor

Cell Transformation, Neoplastic - genetics

Disease Models, Animal

Drug Resistance, Neoplasm

Epithelial-Mesenchymal Transition - genetics

ErbB Receptors - antagonists & inhibitors

ErbB Receptors - genetics

ErbB Receptors - metabolism

Erlotinib Hydrochloride

Female

Gene Expression

Gene Expression Regulation, Neoplastic

Heterografts

Humans

Mice

Neoplasm Metastasis

Neoplasms, Basal Cell - genetics

Neoplasms, Basal Cell - metabolism

Neoplasms, Basal Cell - pathology

Protein Kinase Inhibitors - pharmacology

Quinazolines - pharmacology

Tumor Burden - genetics

Tumor Suppressor Proteins - genetics

Details

Title: Subtitle: The antitumorigenic function of EGFR in metastatic breast cancer is regulated by expression of Mig6
Creators: Michael K Wendt - Purdue University West Lafayette
Whitney K Williams - Purdue University West Lafayette
Pete E Pascuzzi - Purdue University System
Nikolas G Balanis - Case Western Reserve University
Barbara J Schiemann - Case Western Reserve University
Cathleen R Carlin - Case Western Reserve University
William P Schiemann - Case Western Reserve University
Resource Type: Journal article
Publication Details: Neoplasia (New York, N.Y.), Vol.17(1), pp.124-133
DOI: 10.1016/j.neo.2014.11.009
PMID: 25622905
PMCID: PMC4309683
NLM abbreviation: Neoplasia
ISSN: 1476-5586
eISSN: 1476-5586
Grant note: GM081498 / NIGMS NIH HHS T32 HL007653 / NHLBI NIH HHS R01 CA129359 / NCI NIH HHS R00 CA166140 / NCI NIH HHS K99 CA166140 / NCI NIH HHS CA166140 / NCI NIH HHS P30 CA043703 / NCI NIH HHS CA177069 / NCI NIH HHS R01 CA177069 / NCI NIH HHS R01 GM081498 / NIGMS NIH HHS CA129359 / NCI NIH HHS P30 CA023168 / NCI NIH HHS
Language: English
Date published: 01/01/2015
Academic Unit: Internal Medicine
Record Identifier: 9984459628202771

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