The Antitumorigenic Function of EGFR in Metastatic Breast Cancer is Regulated by Expression of Mig6

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

doi:10.1016/j.neo.2014.11.009

Cited by 37 publications

(45 citation statements)

References 32 publications

(68 reference statements)

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“…31 Similarly, in vivo metastatic selection of the heterogeneous MDA-MB-231 TNBC cells is associated with a marked loss of EGFR expression. 31 This discordance in EGFR expression is observed clinically and in mouse models of metastatic colorectal cancer, 40 ovarian cancer 41 and lung cancer. 42 The first observation that metastatic BC cells can have low to undetectable levels of EGFR was reported for the DU4475 (cutaneous metastasis) and AlAb 496 (lung metastasis) cell models in 1982.…”

Section: Potential Mechanisms Of Inherent Resistance To Egfri In Metamentioning

confidence: 99%

The paradoxical functions of EGFR during breast cancer progression

Ali

Wendt

2017

Sig Transduct Target Ther

106

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The epidermal growth factor receptor (EGFR) is one of the most well-studied signaling pathways in cancer progression. As a result, numerous therapeutics including small-molecule inhibitors and monoclonal antibodies have been developed to target this critical oncogenic driver. Several of these EGFR inhibitors (EGFRi) have been evaluated in metastatic breast cancer, as high-level EGFR expression in primary tumors correlates with the highly aggressive basal-like phenotype and predicts for poor patient prognosis. Surprisingly, these trials have been unanimously unsuccessful at improving patient outcomes. Numerous factors, such as lack of proper patient selection may have contributed to the failure of these trials. However, recent findings suggest that there are fundamental changes in EGFR signaling that take place during primary tumor invasion, dissemination and ultimate metastasis of breast cancer cells. Herein, we review the outcomes of EGFR-targeted clinical trials in breast cancer and explore our current understanding of EGFR signaling within primary mammary tumors and how these events are altered in the metastatic setting. Overall, we put forth the hypothesis that fundamental changes in EGFR signaling between primary and metastatic tumors, a process we term the ‘EGFR paradox,’ contribute to the clinically observed inherent resistance to EGFRi. Furthermore, this hypothesis introduces the possibility of utilizing EGFR agonism as a potential therapeutic approach for the treatment of metastatic breast cancer.

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Section: Potential Mechanisms Of Inherent Resistance To Egfri In Metamentioning

confidence: 99%

The paradoxical functions of EGFR during breast cancer progression

Ali

Wendt

2017

Sig Transduct Target Ther

106

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“…However, subsets of cancer cells, including those originating from the breast, respond to epidermal growth factor (EGF) via cell cycle arrest and induction of apoptosis [11][12][13][14] . These observations are corroborated by the antitumor response of in vivo administered EGF 15 .…”

Section: Introductionmentioning

confidence: 99%

“…We have recently shown that EGFR function changes from oncogenic in primary tumors to growth-inhibitory and apoptotic in metastatic tumors 5,19 . The importance of this paradoxical function of EGFR is substantiated by the failure of EGFR inhibition (EGFRi) to improve the clinical outcomes of metastatic breast cancer patients [20][21][22][23][24][25][26][27][28] .…”

Section: Introductionmentioning

confidence: 99%

Biased signaling downstream of epidermal growth factor receptor regulates proliferative versus apoptotic response to ligand

Ali

Brown

Purdy

et al. 2018

Preprint

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Inhibition of EGFR signaling by small molecule kinase inhibitors and monocloncalantibodies has proven effective in the treatment of multiple cancers. In contrast, metastatic breast cancers (BC) derived from EGFR-expressing mammary tumors are inherently resistant to EGFRtargeted therapies. Mechanisms that contribute to this inherent resistance remain poorly defined.Here we show that in contrast to primary tumors, ligand-mediated activation of EGFR in metastatic BC is dominated by STAT1 signaling. This change in downstream signaling leads to apoptosis and growth inhibition in response to EGF in metastatic BC cells. Mechanistically, these changes in downstream signaling result from an increase in the internalized pool of EGFR in metastatic cells, increasing physical access to the nuclear pool of STAT1. Along these lines, an EGFR mutant that is defective in endocytosis is unable to elicit STAT1 phosphorylation and apoptosis. Additionally, inhibition of endosomal signaling using an EGFR inhibitor linked to a nuclear localization signal specifically prevents EGF-induced STAT1 phosphorylation and cell death, without affecting EGFR:ERK1/2 signaling. Pharmacologic blockade of ERK1/2 signaling through the use of the allosteric MEK1/2 inhibitor, trametinib, dramatically biases downstream EGFR signaling toward a STAT1 dominated event, resulting in enhanced EGF-induced apoptosis in metastatic BC cells. Importantly, combined administration of trametinib and EGF also facilitated an apoptotic switch in EGFR-transformed primary tumor cells, but not normal mammary epithelial cells. These studies reveal a fundamental distinction for EGFR function in metastatic BC. Furthermore, the data demonstrate that pharmacological biasing of EGFR signaling toward STAT1 activation is capable of revealing the apoptotic function of this critical pathway.

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“…Accumulated evidences suggest that the MIG6 plays an essential role in suppressing the development, proliferation, and metastasis of NSCLC by inactivating EGFR Maity et al 2015;Izumchenko and Sidransky 2015;). Knockout of the MIG6 gene has also been found to strongly associate with a variety of tumors such as breast cancer (Wendt et al 2015), endometrial cancer (Kim et al 2014) and skin tumor (Ferby et al 2006). The crystal structure of EGFR-MIG6 complex revealed that two separated segments in MIG6 protein, called MIG6 s1 (residues 336-361) and MIG6 s2 (residues 376-398), interact with the C-lobe of EGFR kinase domain ( Figure 1) (Park et al 2015).…”

Section: Introductionmentioning

confidence: 99%

Conversion of MIG6 peptide from the nonbinder to binder of lung cancer-related EGFR by phosphorylation and cyclization

Wei

2016

Artificial Cells, Nanomedicine, and Biotechnology

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Development of chemical drugs and biologic agents to target human epidermal growth factor receptor (EGFR) has long been established as a promising therapeutic strategy for lung cancer. Previously, it was found that the tumor-suppressor protein MIG6 is a negative regulator of the EGFR kinase, which can bind at the activation interface of asymmetric dimer of EGFR kinase domains to disrupt EGFR dimerization and then inactivate the kinase. The protein adopts two separated segments, that is, MIG6 and MIG6, to directly interact with EGFR. Here, by computational modeling and analysis of the intermolecular interaction between EGFR kinase domain and MIG6 peptide, we demonstrated that the dephosphorylated MIG6 peptide can be converted from nonbinder to weak binder and then to moderate binder of EGFR by phosphorylation and cyclization, respectively; the former introduces strong electrostatic potential to EGFR-peptide complex by forming two geometrically satisfactory salt bridges across the complex interface, while the latter minimizes entropy penalty upon the binding of highly flexible peptide to EGFR. Subsequently, the linear phosphorylated and dephosphorylated peptides and phosphorylated cyclic peptide were synthesized and purified, and their binding affinities to the recombinant protein of human EGFR kinase domain were determined by fluorescence polarization titration. As expected theoretically, the linear dephosphorylated peptide has no observable binding to the kinase, and further phosphorylation and cyclization can confer, respectively, low and moderate affinities to the peptide, suggesting a good consistence between the computational analysis and experimental assay.

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The Antitumorigenic Function of EGFR in Metastatic Breast Cancer is Regulated by Expression of Mig6

Cited by 37 publications

References 32 publications

The paradoxical functions of EGFR during breast cancer progression

The paradoxical functions of EGFR during breast cancer progression

Biased signaling downstream of epidermal growth factor receptor regulates proliferative versus apoptotic response to ligand

Conversion of MIG6 peptide from the nonbinder to binder of lung cancer-related EGFR by phosphorylation and cyclization

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