Role of epidermal growth factor receptor in breast cancer

Masuda, Hiroko; Zhang, Dongwei; Bartholomeusz, Chandra; Doihara, Hiroyoshi; Hortobágyi, Gabriel N.; Ueno, Naoto T.

doi:10.1007/s10549-012-2289-9

Cited by 623 publications

(513 citation statements)

References 83 publications

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“…Although HER2 is classically considered upstream of PI3K, these results indicate that under certain conditions, interactions between mutant PIK3CA and mutant HER2 may lead to "rewiring" and dysregulation of signaling pathways. Similar pathway dysregulation has been reported in other studies (17,21,22). Because PIK3CA mutations have been shown to confer EGFindependent growth properties to MCF-10A cells, we tested if HER2 mutations could augment this phenotype.…”

Section: Acinar Morphology and Anchorage Independent Growth In Mcf7supporting

confidence: 74%

HER2 missense mutations have distinct effects on oncogenic signaling and migration

Zabransky

Yankaskas

Cochran

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Recurrent human epidermal growth factor receptor 2 (HER2) missense mutations have been reported in human cancers. These mutations occur primarily in the absence of HER2 gene amplification such that most HER2-mutant tumors are classified as "negative" by FISH or immunohistochemistry assays. It remains unclear whether nonamplified HER2 missense mutations are oncogenic and whether they are targets for HER2-directed therapies that are currently approved for the treatment of HER2 gene-amplified breast cancers. Here we functionally characterize HER2 kinase and extracellular domain mutations through gene editing of the endogenous loci in HER2 nonamplified human breast epithelial cells. In in vitro and in vivo assays, the majority of HER2 missense mutations do not impart detectable oncogenic changes. However, the HER2 V777L mutation increased biochemical pathway activation and, in the context of a PIK3CA mutation, enhanced migratory features in vitro. However, the V777L mutation did not alter in vivo tumorigenicity or sensitivity to HER2-directed therapies in proliferation assays. Our results suggest the oncogenicity and potential targeting of HER2 missense mutations should be considered in the context of cooperating genetic alterations and provide previously unidentified insights into functional analysis of HER2 mutations and strategies to target them. A great success in the treatment of breast cancer has come from the identification of human epidermal growth factor receptor 2 (HER2)/Neu (ERBB2) amplification/overexpression as a targetable driver in ∼20% of breast cancers (1). HER2 is a member of the ErbB family of transmembrane receptor tyrosine kinases, which includes the epidermal growth factor receptor (EGFR/ErbB1), HER3 (ErbB3), and HER4 (ErbB4) (2). Activation of ErbB signaling causes receptor tyrosine autophosphorylation and induces interactions with cytoplasmic signal transduction partners that promote a wide variety of cellular processes including proliferation, motility, and escape from apoptosis. In addition to their key role in normal cellular growth and maintenance, the dysregulation of ErbB receptors has been extensively implicated in the development of numerous cancers (1).Whereas overexpression or amplification of HER2 has been well described to deregulate ErbB signaling, cancer genome sequencing studies have demonstrated that somatic point mutations in the HER2 gene occur in a number of cancers, including 2-4% of breast cancers (3-6). Importantly, these mutations are most often found in patients as single copies without amplification/overexpression of HER2 (HER2-"negative" breast cancers), though HER2 protein expression is often still present. Overexpression studies have implicated a number of these mutations as activating and oncogenic (4, 7-9). Additionally, one mutation, L755S, has been described to be associated with lapatinib resistance when overexpressed (4, 10).Past studies comparing overexpression of a mutant cDNA to single nucleotide knockin of mutant oncogenes have shown dramatic differences ...

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Section: Acinar Morphology and Anchorage Independent Growth In Mcf7supporting

confidence: 74%

HER2 missense mutations have distinct effects on oncogenic signaling and migration

Zabransky

Yankaskas

Cochran

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Previous studies have revealed a role for the ERK/MAPK pathway in the evasion of anoikis. 21,24,27,32 In order to assess the activation of ERK signaling in IBC cells, we examined phospho-ERK levels in KPL-4 cells deficient in ErbB2 or SUM149 cells deficient in EGFR. In each case, we discovered that the deficiency in receptor tyrosine kinase expression (i.e., ErbB2 in KPL-4 and EGFR in SUM149) resulted in a concomitant loss of phospho-ERK (Figure 3a).…”

Section: Resultsmentioning

confidence: 99%

“…17 It has become clear that tumor progression and metastasis require cancer cells to inhibit anoikis, oftentimes through alterations in intracellular signaling pathways. [18][19][20] Interestingly, previous studies have shown that ErbB2 and EGFR, which are hyperactivated in a substantial percentage of IBC patients, 21 can effectively antagonize the anoikis program to facilitate anchorage-independent growth. [22][23][24][25][26][27][28] However, a detailed examination of the molecular mechanisms underlying anoikis inhibition in IBC cells has yet to be completed.…”

mentioning

confidence: 99%

Anoikis evasion in inflammatory breast cancer cells is mediated by Bim-EL sequestration

et al. 2014

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Inflammatory breast cancer (IBC) is a rare and highly invasive type of breast cancer, and patients diagnosed with IBC often face a very poor prognosis. IBC is characterized by the lack of primary tumor formation and the rapid accumulation of cancerous epithelial cells in the dermal lymphatic vessels. Given that normal epithelial cells require attachment to the extracellular matrix (ECM) for survival, a comprehensive examination of the molecular mechanisms underlying IBC cell survival in the lymphatic vessels is of paramount importance to our understanding of IBC pathogenesis. Here we demonstrate that, in contrast to normal mammary epithelial cells, IBC cells evade ECM-detachment-induced apoptosis (anoikis). ErbB2 and EGFR knockdown in KPL-4 and SUM149 cells, respectively, causes decreased colony growth in soft agar and increased caspase activation following ECM detachment. ERK/MAPK signaling was found to operate downstream of ErbB2 and EGFR to protect cells from anoikis by facilitating the formation of a protein complex containing Bim-EL, LC8, and Beclin-1. This complex forms as a result of Bim-EL phosphorylation on serine 59, and thus Bim-EL cannot localize to the mitochondria and cause anoikis. These results reveal a novel mechanism that could be targeted with innovative therapeutics to induce anoikis in IBC cells.

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“…It was suggested that EGFR activation drives migration and invasion of tumor cells through epithelial-mesenchymal transition and alters chemosensitivity by rewiring the apoptotic signaling network. 35 However, the utility of high EGFR copy number as a predictive biomarker for EGFR-targeted therapy and as a prognostic factor for triple-negative breast cancer should be validated in large studies.…”

Section: Discussionmentioning

confidence: 99%

High EGFR gene copy number predicts poor outcome in triple-negative breast cancer

Park¹,

et al. 2014

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Epidermal growth factor receptor (EGFR) is frequently overexpressed in triple-negative breast cancer and is emerging as a therapeutic target. EGFR gene copy number alteration and mutation are highly variable and scientists have been challenged to define their prognostic significance in triple-negative breast cancer. We examined EGFR protein expression, EGFR gene copy number alteration and mutation of exon 18 to 21 in 151 cases of triple-negative breast cancer and correlated these findings with clinical outcomes. In addition, intratumoral agreement of EGFR protein overexpression and gene copy number alteration was evaluated. EGFR overexpression was found in 97 of 151 cases (64%) and high EGFR gene copy number was detected in 50 cases (33%), including 3 gene amplification (2%) and 47 high polysomy (31%). Five EGFR mutations were detected in 4 of 151 cases (3%) and included G719A in exon 18 (n ¼ 1), V786M in exon 20 (n ¼ 1), and L858R in exon 21 (n ¼ 3). One case had two mutations (G719A and L858R). High EGFR copy number, but not EGFR mutation, correlated with EGFR protein overexpression. Intratumoral heterogeneity of EGFR protein overexpression and EGFR copy number alteration was not significant. In survival analyses, high EGFR copy number was found to be an independent prognostic factor for poor disease-free survival in patients with triple-negative breast cancer. Our findings showed that EGFR mutation was a rare event, but high EGFR copy number was relatively frequent and correlated with EGFR overexpression in triple-negative breast cancer. Moreover, high EGFR copy number was associated with poor clinical outcome in triple-negative breast cancer, suggesting that evaluation of EGFR copy number may be useful for predicting outcomes in patients with triple-negative breast cancer and for selecting patients for anti-EGFR-targeted therapy.

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Role of epidermal growth factor receptor in breast cancer

Cited by 623 publications

References 83 publications

HER2 missense mutations have distinct effects on oncogenic signaling and migration

HER2 missense mutations have distinct effects on oncogenic signaling and migration

Anoikis evasion in inflammatory breast cancer cells is mediated by Bim-EL sequestration

High EGFR gene copy number predicts poor outcome in triple-negative breast cancer

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