HER-2/neu expression: A major prognostic factor in endometrial cancer

Hetzel, David J.; Wilson, Timothy O.; Keeney, Gary L.; Roche, Patrick C.; Stephen, S.; Podratz, Karl C.

doi:10.1016/0090-8258(92)90103-p

Cited by 203 publications

(68 citation statements)

References 17 publications

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“…In their subsequent study, they found almost complete concordance between the gene amplification detected by Southern blot analyses and the overexpression as determined by Northern blot, Western blot and/or immunohistochemical analyses (4). Since then, most, but not all, investigators have found that either amplification or increased expression of the c-erbB-2 gene correlates with poor prognosis in many different human primary tumors including ovarian (5), pulmonary (6) and endometrial carcinomas (7). In non-small cell lung carcinomas (NSCLCs), some investigators reported that more than half of the tumors overexpressed the oncoprotein (8); however, according to others, its frequency was less than 2% (9).…”

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confidence: 91%

Protein Overexpression and Gene Amplification of c-erbB-2 in Pulmonary Carcinomas: A Comparative Immunohistochemical and Fluorescence In Situ Hybridization Study

et al. 2001

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Amplification of the c-er bB-2 gene (located on 17q11.2-12) is accompanied by overexpression of its cell surface receptor product, p185 ERBB2 . In pulmonary carcinomas, however, there has been disagreement between the reported frequencies of gene amplification and overexpression. To clarify their relationship, the correlation between the cellular expression of p185 ERBB2 and the level of c-erb B-2 gene amplification was studied. A total of 195 pulmonary carcinomas (182 primary and 13 metastatic) were examined immunohistochemically using a polyclonal antibody, which recognizes the internal domain of the human c-erb B-2 protein, and positive tumors were further examined for the gene amplification by dual-color fluorescence in situ hybridization using probes for centromere 17 and 17q11.2-12. By immunohistochemistry, distinct membrane staining was found in an adenocarcinoma, a large cell carcinoma and a metastatic carcinoma from the breast, and cytoplasmic and/or faint membranous staining was observed in 23 nonsmall cell lung carcinomas. It was in the two primaries and the metastatic carcinoma that more than 8-fold amplification of c-erb B-2 was found by fluorescence in situ hybridization. Especially, in the two primary carcinomas, tumor cells had amplified genes with the signals forming one or two clusters, indicating that the amplified gene was present in homogeneously staining regions. Among the 23 tumors, three tumors showed low-level amplification (less than 3-fold), which was differentiated from polysomy 17 found in the other two. In the 30 nonsmall cell lung carcinomas selected at random from 151 with negative immunostaining, there were five trisomy 17, but no tumors with the gene amplification. This suggests that although c-erb B-2 amplification in pulmonary carcinoma is rare, it occurs in the form of a homogeneously staining region and is thought to control the overexpression of the protein in the cell membrane. New adjuvant therapy using a humanized antibody to the oncoprotein may be beneficial to patients with these tumors.

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confidence: 91%

Protein Overexpression and Gene Amplification of c-erbB-2 in Pulmonary Carcinomas: A Comparative Immunohistochemical and Fluorescence In Situ Hybridization Study

et al. 2001

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“…HER2/Neu overexpression has been demonstrated in many cancers and is linked to advanced stage and poor prognosis (40,41). Furthermore, ER81, or the related ETS proteins ERM and PEA3, appear to be overexpressed in HER2/Neu-overexpressing human breast cancers, and transgenic mice overexpressing HER2/Neu in mammary tissue accordingly display a coordinate up-regulation of ER81, ERM, and PEA3 (42, 45, 74).…”

Section: Smad7 Activation By Her2/neu Tak1 and Er81mentioning

confidence: 99%

“…Another important activator of MAPK pathways is HER2/ Neu, a transmembrane receptor kinase overexpressed in 20 -30% of breast and ovarian cancers and 10 -15% of endometrial cancers (40,41). Clinically, HER2/Neu overexpression in tumors is associated with high grade, advanced stage, and poor prognosis.…”

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confidence: 99%

HER2/Neu- and TAK1-mediated Up-regulation of the Transforming Growth Factor β Inhibitor Smad7 via the ETS Protein ER81

Dowdy¹,

Mariani²,

Janknecht

2003

Journal of Biological Chemistry

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The cytokine transforming growth factor ␤ (TGF-␤) plays an important role in preventing tumor formation by blocking cell cycle progression. Accordingly, many cancers demonstrate mutations in TGF-␤ signaling components or enhanced expression of inhibitors of the TGF-␤ pathway such as Smad7. In this report we show that the oncoprotein HER2/Neu is able to collaborate with the ETS transcription factor ER81 to activate Smad7 transcription in breast, endometrial, and ovarian cancer cell lines. ER81 binds to two ETS sites within the Smad7 promoter, and mutation of one of these ETS sites greatly decreases Smad7 induction by HER2/Neu and ER81. Furthermore, we show that Smad7 activation involves the processing of signals from HER2/Neu to ER81 via the ERK mitogen-activated protein kinase pathway. Thus, we have uncovered a novel mechanism by which oncogenic HER2/Neu, in collaboration with ER81, can induce carcinogenesis through Smad7 upregulation. Moreover, we show that TAK1, a TGF-␤-activated protein kinase, stimulates ER81 via the p38 mitogen-activated protein kinase pathway and thereby induces the Smad7 promoter. This suggests that attenuation of TGF-␤ signaling by activating Smad7 transcription may proceed not only through TGF-␤ receptorregulated Smad proteins but also through an independent pathway involving ER81 and TAK1.

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“…In contrast, p53 mutations, which are not usually seen in type I EC have been identified in most cases of type II EC (Acharya et al, 2005). Moreover, HER2 amplification/overexpression has been associated with type II EC (Hetzel et al, 1992;Santin et al, 2005;Morrison et al, 2006;Grushko et al, 2008). However, the exact frequency of HER2 amplification/overexpression in type II EC remains controversial.…”

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confidence: 97%

HER2 gene amplification and EGFR expression in a large cohort of surgically staged patients with nonendometrioid (type II) endometrial cancer

et al. 2008

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Type II endometrial cancers (uterine serous papillary and clear cell histologies) represent rare but highly aggressive variants of endometrial cancer (EC). HER2 and EGFR may be differentially expressed in type II EC. Here, we evaluate the clinical role of HER2 and EGFR in a large cohort of surgically staged patients with type II (nonendometrioid) EC and compare the findings with those seen in a representative cohort of type I (endometrioid) EC. In this study HER2 gene amplification was studied by fluorescence in situ hybridisation (FISH) and EGFR expression by immunohistochemistry. Tissue microarrays were constructed from 279 patients with EC (145 patients with type I and 134 patients with type II EC). All patients were completely surgically staged and long-term clinical follow up was available for 258 patients. The rate of HER2 gene amplification was significantly higher in type II EC compared with type I EC (17 vs 1%, Po0.001). HER2 gene amplification was detected in 17 and 16% of the cases with uterine serous papillary and clear cell type histology, respectively. In contrast, EGFR expression was significantly lower in type II compared with type I EC (34 vs 46%, P ¼ 0.041). EGFR expression but not HER2 gene amplification was significantly associated with poor overall survival in patients with type II EC, (EGFR, median survival 20 vs 33 months, P ¼ 0.028; HER2, median survival 18 vs 29 months, P ¼ 0.113) and EGFR expression retained prognostic independence when adjusting for histology, stage, grade, and age (EGFR, P ¼ 0.0197; HER2, P ¼ 0.7855). We conclude that assessment of HER2 gene amplification and/or EGFR expression may help to select type II EC patients who could benefit from therapeutic strategies targeting both HER2 and EGFR.

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HER-2/neu expression: A major prognostic factor in endometrial cancer

Cited by 203 publications

References 17 publications

Protein Overexpression and Gene Amplification of c-erbB-2 in Pulmonary Carcinomas: A Comparative Immunohistochemical and Fluorescence In Situ Hybridization Study

Protein Overexpression and Gene Amplification of c-erbB-2 in Pulmonary Carcinomas: A Comparative Immunohistochemical and Fluorescence In Situ Hybridization Study

HER2/Neu- and TAK1-mediated Up-regulation of the Transforming Growth Factor β Inhibitor Smad7 via the ETS Protein ER81

HER2 gene amplification and EGFR expression in a large cohort of surgically staged patients with nonendometrioid (type II) endometrial cancer

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