The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesis

Moasser, Mark M.

doi:10.1038/sj.onc.1210477

Cited by 912 publications

(776 citation statements)

References 202 publications

(197 reference statements)

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“…The tumorigenic potential of HER2 is solidly supported by experimental models (Moasser, 2007). This by itself proposes HER2 as a possible target for anti-cancer drugs.…”

Section: Tumor Dependence On Her2mentioning

confidence: 92%

“…In addition, analysis of human breast cancers has shown that amplification of the HER2 locus is an early event in human carcinogenesis and along with the experimental evidence confirming its potently transforming functions, this makes a highly compelling case, implicating HER2 overexpression in the genesis of these human cancers. The signaling functions of HER2, the body of evidence confirming the transforming functions of HER2, the numerous proposed mechanisms mediating its transforming functions, and the data establishing the relevance of these findings to human cancer pathogenesis were discussed in depth previously (Moasser, 2007). A direct consequence of the HER2 oncogene hypothesis of human cancer was that inhibitors of oncogenic HER2 would be highly effective treatment for HER2-driven cancers.…”

Section: Introductionmentioning

confidence: 99%

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Targeting the function of the HER2 oncogene in human cancer therapeutics

2007

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“…The tumorigenic potential of HER2 is solidly supported by experimental models (Moasser, 2007). This by itself proposes HER2 as a possible target for anti-cancer drugs.…”

Section: Tumor Dependence On Her2mentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Targeting the function of the HER2 oncogene in human cancer therapeutics

2007

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“…The HER2 gene is amplified and overexpressed in about 25% of breast cancers, conferring a more aggressive biology (Slamon et al, 1987). The aetiologic role of HER2 in mammary tumorigenesis has been confirmed by numerous mouse models of constitutively activated HER2 (or its rodent counterpart Neu) (Ursini- Siegel et al, 2007;Moasser, 2007a). HER2 overexpression is potently transforming in numerous cell culture models and in numerous transgenic mouse models (Moasser, 2007a).…”

Section: Her2-driven Breast Cancermentioning

confidence: 99%

Targeting HER proteins in cancer therapy and the role of the non-target HER3

2007

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Members of the human epidermal growth factor receptor (HER) family have been of considerable interest in the cancer arena due to their potential to induce tumorigenesis when their signalling functions are deregulated. The constitutive activation of these proteins is seen in a number of different common cancer subtypes, and in particular EGFR and HER2 have become highly pursued targets for anti-cancer drug development. Clinical studies in a number of different cancers known to be driven by EGFR or HER2 show mixed results, and further mechanistic understanding of drug sensitivity and resistance is needed to realise the full potential of this treatment modality. Signalling in trans is a key feature of HER family signalling, and the activation of the PI3K/Akt pathway, so critically important in tumorigenesis, is driven predominantly through phosphorylation in trans of the kinase inactive member HER3. An increasing body of evidence shows that HER3 plays a critical role in EGFR-and HER2-driven tumours. In particular, HER3 lies upstream of a critically important tumorigenic signalling pathway with extensive ability for feedback and cross-talk signalling, and targeting approaches that fail to account for this important trans-target of EGFR and HER2 can be undermined by its resiliency and resourcefulness. Since HER3 is kinase inactive, it is not a direct target of kinase inhibitors and not presently an easily drugable target. This review presents the current evidence highlighting the role of HER3 in tumorigenesis and its role in mediating resistance to inhibitors of EGFR and HER2.

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“…It was first implicated in the pathogenesis of human breast cancer 25 years ago. 11 In patients with breast cancer, ERBB2 amplification is associated with poor prognosis. 12 However, ERBB2-targeted therapy with the anti-ERBB2 antibody trastuzumab has resulted in significantly longer survival when combined with standard chemotherapy in patients whose breast tumors exhibit ERBB2 amplification compared with patients whose tumor lack ERBB2 amplification.…”

mentioning

confidence: 99%

Outcome of patients with micropapillary urothelial carcinoma following radical cystectomy: ERBB2 (HER2) amplification identifies patients with poor outcome

et al. 2014

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Micropapillary urothelial carcinoma exhibits amplification of the human epidermal growth factor receptor, ERBB2(HER2), and overexpression of the ERBB2 protein product. The clinical significance of this has yet to be established. The objective of this study was to examine ERBB2 amplification and protein expression in micropapillary urothelial carcinoma and stage-matched typical urothelial carcinoma treated by radical cystectomy to assess the frequency of amplification and protein expression, and to determine the association with cancer-specific survival. Pathologic material and data from patients undergoing cystectomy at Mayo Clinic between 1980 and 2008 were reviewed. ERBB2 amplification by fluorescence in situ hybridization (FISH) and protein expression by immunohistochemistry were assessed. Univariate and multivariate Cox proportional hazards regression models were used to evaluate for associations of ERBB2 amplification and protein expression with survival. ERBB2 amplification was identified in 9 (15%) of 61 micropapillary carcinomas compared with 9 (9%) of 100 urothelial carcinomas. In patients with micropapillary carcinoma, ERBB2 amplification was associated with a nearly threefold increased risk of cancer death. ERBB2 amplification (hazard ratio 4.3; P ¼ 0.0008) remained associated with an increased risk of death from bladder cancer among patients with micropapillary urothelial carcinoma on multivariate analysis. The association of cancer-specific survival and ERBB2 amplification was not seen in patients with urothelial carcinoma. ERBB2 immunohistochemistry correlated with ERBB2 amplification but there was no association of ERBB2 protein expression and survival. ERBB2 amplification is more frequent in micropapillary urothelial carcinoma than typical urothelial carcinoma, and patients with micropapillary carcinoma who have ERBB2 amplification have worse cancer-specific survival than those who do not. Identification of ERBB2 amplification in micropapillary carcinoma could provide important prognostic information and possibly provide a role for ERBB2 targeted therapy.

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The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesis

Cited by 912 publications

References 202 publications

Targeting the function of the HER2 oncogene in human cancer therapeutics

Targeting the function of the HER2 oncogene in human cancer therapeutics

Targeting HER proteins in cancer therapy and the role of the non-target HER3

Outcome of patients with micropapillary urothelial carcinoma following radical cystectomy: ERBB2 (HER2) amplification identifies patients with poor outcome

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