Amplification and protein over-expression of the neu/HER-2/c-erbB-2 protooncogene in human breast carcinomas: relationship to loss of gene sequences on chromosome 17, family history and prognosis

Børresen, Anne Lise; Ottestad, Lars; Gaustad, Astrid; Andersen, Tone Ikdahl; Heikkilä, Reino; Jahnsen, Tore; Tveit, Kjell Magne; Nesland, Jahn M.

doi:10.1038/bjc.1990.334

Cited by 59 publications

(25 citation statements)

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“…This is consistent with some reports (B0rrensen et al, 1990;Varley et al, 1991), but not others (Sato et al, 1991;Knyazev et al, 1993). Bivariate analyses suggested that LOH for DI 7S5 and erbB-2 amplification are each independently associated with a poor prognosis (Table II).…”

Section: Discussionsupporting

confidence: 82%

“…Previous studies correlating chromosome 17p LOH with clinicopathological variables in breast cancer have generally failed to distinguish between events at TP53 and at the more distal locus (B0rrensen et al, 1990;Cropp et al, 1991;Varley et al, 1991). There have been two reports of an association between LOH in the telomeric region of chromosome 17p, but not at TP53, and lymph node status (Andersen et al, 1992;Takita et al, 1992).…”

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confidence: 99%

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Allelic loss on distal chromosome 17p is associated with poor prognosis in a group of Brazilian breast cancer patients

Nagai

Pacheco²,

Brentani³

et al. 1994

Br J Cancer

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Summary We examined loss of heterozygosity (LOH) for two loci on chromosome 17p (D17S5 and TP53), and erbB-2 gene amplification, in primary breast cancers from 67 Brazilian patients. We identified two distinct regions of LOH on chromosome 17p, one spanning TP53 and the other a more telomeric region (D17S5). Based on a short-term follow-up, Kaplan-Meier analyses of patients' disease-free survival showed that patients with LOH for D17S5, but retaining heterozygosity for TP53, were at higher risk of recurrence (P = 0.007) than those who retained heterozygosity for D17S5. Bivariate analyses indicated that patients with LOH for D17S5 alone had an increased risk of recurrence (hazard ratio = 7.2) over patients with erbB-2 amplification (hazard ratio = 3.7), when compared with patients with neither alteration (hazard ratio = 1.0). Further, lymph node-positive patients whose tumours had both LOH for D17S5 and erbB-2 gene amplification had a higher risk of recurrence than patients whose tumours had neither of these genetic alterations. Our data confirm previous reports of a putative tumour-suppressor gene, distinct from TP53, on distal chromosome 17p which is associated with breast cancer. They further suggest that LOH for loci in this region may provide an independent indicator to identify patients with poor prognosis.

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Section: Discussionsupporting

confidence: 82%

mentioning

confidence: 99%

Allelic loss on distal chromosome 17p is associated with poor prognosis in a group of Brazilian breast cancer patients

Nagai

Pacheco²,

Brentani³

et al. 1994

Br J Cancer

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“…The observation that all c-erbB-2 gene amplified tumours were of ductal type is in agreement with previous reports (30,33). Furthermore, the observation that all int-2 amplified tumours were ER positive (8/8) is interesting.…”

Section: Discussionsupporting

confidence: 81%

“…The contamination of normal cells was scored by eye for each sample, and most samples contained more than 50% tumour cells, D N A analyses. DNA was extracted from tissues using standard procedures (phenol/chloroform extraction and EtOH precipitation) after mincing the tissue by a scalpel, followed by digestion with proteinase K in 2% sarcosyl over night at 4°C as previously described (33). Amplification of the c-erbB-2 gene was analysed by Southern technique after digestion with EcoRI.…”

Section: Methodsmentioning

confidence: 99%

Amplification of c-erbB-2, int-2 and c-myc Genes in Node-Negative Breast Carcinomas: Relationship to Prognosis

et al. 1993

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“…[7][8][9][10] The transforming ability of HER2 has been associated with enhanced cell survival and mitogenic signaling pathways. Amplification of HER2 is observed in cancers of the breast, [11][12][13][14][15] ovary, 12,16 lung 17 and stomach; 18 and its overexpression predicts poor prognosis in several human cancers. 11,16,19 -23 At the molecular level, HER2 overexpression can deregulate the G 1 -S transition by downregulating p27 Kip1 and stimulating the cyclin E-cdk2 complex.…”

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confidence: 99%

Enhancement of the p27^Kip1‐mediated antiproliferative effect of trastuzumab (Herceptin) on HER2‐overexpressing tumor cells

Marcheş

Uhr

2004

Intl Journal of Cancer

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The oncogenic activity of the overexpressed HER2 tyrosine kinase receptor requires its localization in the plasma membrane. The antitumor effect of anti-HER2 antibodies (Abs) is mainly dependent on receptor downregulation and comprises p27 Kip1 -mediated G 1 cell cycle arrest. However, one major limitation of anti-HER2 therapy is the reversibility of tumor growth inhibition after discontinuation of treatment caused by the mitogenic signaling associated with cell surface receptor re-expression. We found that the level of Key words: HER2; receptor internalization; p27Kip1 ; G 1 arrestThe neu (c-ErbB-2, HER2) proto-oncogene, encoding a 185 kDa RTK, is a member of the EGF receptor family, which includes ErbB-1 (HER1, EGFR), ErbB-3 (HER3) and ErbB-4 (HER4). 1 Activation of RTKs is dependent on ligand-mediated homodimerization and subsequent autophosphorylation and transphosphorylation of the intracellular kinase domains of the paired receptors. However, HER2 may be activated even in the absence of a direct ligand because it forms heterodimeric complexes with its family members HER1, HER3 and HER4 2-7 upon ligand binding to the ectodomain of these receptors. Once recruited into these heterodimeric complexes, HER2 can modulate ligand-mediated receptor internalization to the recycling route and amplify signal transduction. 7-10 The transforming ability of HER2 has been associated with enhanced cell survival and mitogenic signaling pathways. Amplification of HER2 is observed in cancers of the breast, 11-15 ovary, 12,16 lung 17 and stomach; 18 and its overexpression predicts poor prognosis in several human cancers. 11,16,19 -23 At the molecular level, HER2 overexpression can deregulate the G 1 -S transition by downregulating p27Kip1 and stimulating the cyclin E-cdk2 complex. 24 The crucial role of p27 Kip1 in HER2-mediated transformation is consistent with clinical observations that a decreased p27Kip1 protein level in breast cancer is associated with poor prognosis. 25 The key role of HER2 in signaling cell proliferation and transformation made it an attractive therapeutic target in HER2-overexpressing human tumors. MAbs directed against the HER2 ectodomain could specifically inhibit the growth of tumor cells overexpressing HER2. 26 -30 The major mechanism of anti-HER2-mediated inhibition of cell transformation is suppression of HER2 expression on the cell surface 28,31-34 due to Ab-simulated endocytosis of the receptor via coated pits. 35,36 Indeed, retention of nascent HER2 in the endoplasmic reticulum reversed the HER2-mediated transformation associated with cell surface localization. 37 One such potent anti-HER2 Ab, 4D5, 38 was humanized; 39 and the resulting Ab, HCT, is clinically used for the therapy of HER2-overexpressing metastatic breast cancers. 40,41 HCT, like its parental Ab 4D5, markedly downregulates HER2 expression by stimulating receptor endocytosis 42 and thereby arrests cells in the G 1 phase of the cycle via p27 Kip1 . 24,43 However, monotherapy with HCT has limited antitumor effects 44 and requir...

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Amplification and protein over-expression of the neu/HER-2/c-erbB-2 protooncogene in human breast carcinomas: relationship to loss of gene sequences on chromosome 17, family history and prognosis

Cited by 59 publications

References 18 publications

Allelic loss on distal chromosome 17p is associated with poor prognosis in a group of Brazilian breast cancer patients

Allelic loss on distal chromosome 17p is associated with poor prognosis in a group of Brazilian breast cancer patients

Amplification of c-erbB-2, int-2 and c-myc Genes in Node-Negative Breast Carcinomas: Relationship to Prognosis

Enhancement of the p27^Kip1‐mediated antiproliferative effect of trastuzumab (Herceptin) on HER2‐overexpressing tumor cells

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Amplification and protein over-expression of the neu/HER-2/c-erbB-2 protooncogene in human breast carcinomas: relationship to loss of gene sequences on chromosome 17, family history and prognosis

Cited by 59 publications

References 18 publications

Allelic loss on distal chromosome 17p is associated with poor prognosis in a group of Brazilian breast cancer patients

Allelic loss on distal chromosome 17p is associated with poor prognosis in a group of Brazilian breast cancer patients

Amplification of c-erbB-2, int-2 and c-myc Genes in Node-Negative Breast Carcinomas: Relationship to Prognosis

Enhancement of the p27Kip1‐mediated antiproliferative effect of trastuzumab (Herceptin) on HER2‐overexpressing tumor cells

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Product

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Enhancement of the p27^Kip1‐mediated antiproliferative effect of trastuzumab (Herceptin) on HER2‐overexpressing tumor cells