HER-2 overexpression is an independent marker of poor prognosis of advanced primary ovarian carcinoma: a multicenter study of the GINECO group

Camilleri-Broët, Sophie; Hardy‐Bessard, Anne‐Claire; Tourneau, A. Le; Paraïso, D.; Levrel, Olivier; Leduc, Bernard; Bain, Stacey; Orfeuvre, Hubert; Audouin, Josée; Pujade-Lauraine, Éric

doi:10.1093/annonc/mdh021

Cited by 96 publications

(73 citation statements)

References 26 publications

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“…In other studies, the percentage of c-erb-B2-positive tumors ranged from 15% to 30%. 12,21,22 It is noteworthy that c-erb-B2 overexpression in our series was observed only in carcinomas: mostly in highgrade carcinomas. Surprisingly, despite this correlation with aggressive morphology, results of the survival study did not indicate statistical significance.…”

Section: Discussionmentioning

confidence: 51%

“…9 Moreover, p70S6K and eIF4E can be activated by pathways that are independent of mTOR, including the Ras-Raf-MEK-ERK pathway. 10 In previous studies, it was observed that epidermal growth factor receptor (EGFR), c-erb-B2, protein kinase B (AKT), and ERK were expressed frequently in ovarian neoplasms [11][12][13][14] ; however, downstream effectors have not been characterized well in these tumors. We hypothesized that very few factors should exist downstream that could relay the oncogenic signal to the ribosomes or nucleus, regardless of the individual oncogenic alterations upstream.…”

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confidence: 99%

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Phosphorylated 4E binding protein 1: A hallmark of cell signaling that correlates with survival in ovarian cancer

Castellví

García

Rojo

et al. 2006

Cancer

163

114

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BACKGROUND.Growth factor receptors and cell signaling factors play a crucial role in human carcinomas and have been studied in ovarian tumors with varying results. Cell signaling involves multiple pathways and a myriad of factors that can be mutated or amplified. Cell signaling is driven through the mammalian target of rapamycin (mTOR) and extracellular regulated kinase (ERK) pathways and by some downstream molecules, such as 4E binding protein 1 (4EBP1), eukaryotic initiation factor 4E, and p70 ribosomal protein S6 kinase (p70S6K). The objectives of this study were to analyze the real role that these pathways play in ovarian cancer, to correlate them with clinicopathologic characteristics, and to identify the factors that transmit individual proliferation signals and are associated with pathologic grade and prognosis, regardless specific oncogenic alterations upstream.METHODS.One hundred twenty‐nine ovarian epithelial tumors were studied, including 20 serous cystadenomas, 7 mucinous cystadenomas, 11 serous borderline tumors, 16 mucinous borderline tumors, 29 serous carcinomas, 16 endometrioid carcinomas, 15 clear cell carcinomas, and 15 mucinous carcinomas. Tissue microarrays were constructed, and immunohistochemistry for the receptors epidermal growth factor receptor (EGFR) and c‐erb‐B2 was performed and with phosphorylated antibodies for protein kinase B (AKT), 4EBP1, p70S6K, S6, and ERK.RESULTS.Among 129 ovarian neoplasms, 17.8% were positive for c‐erb‐B2, 9.3% were positive for EGFR, 47.3% were positive for phosphorylated AKT (p‐AKT), 58.9% were positive for p‐ERK, 41.1% were positive for p‐4EBP1, 26.4% were positive for p70S6K, and 15.5% were positive for p‐S6. Although EGFR, p‐AKT, and p‐ERK expression did not differ between benign, borderline, or malignant tumors, c‐erb‐B2, p‐4EBP1, p‐p70S6K, and p‐S6 were expressed significantly more often in malignant tumors. Only p‐4EBP1 expression demonstrated prognostic significance (P = .005), and only surgical stage and p‐4EBP1 expression had statistical significance in the multivariate analysis.CONCLUSIONS.In patients with ovarian carcinoma, significant expression of p‐4EBP1 was associated with high‐grade tumors and a poor prognosis, regardless other oncogenic alterations upstream. This finding supports the study of this factor as a hallmark or pivotal factor in cell signaling in ovarian carcinoma that may crucial in the transmission of the proliferation cell signal and may reflect the real oncogenic role of this pathway in ovarian tumors. Cancer 2006. © 2006 American Cancer Society.

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Section: Discussionmentioning

confidence: 51%

mentioning

confidence: 99%

Phosphorylated 4E binding protein 1: A hallmark of cell signaling that correlates with survival in ovarian cancer

Castellví

García

Rojo

et al. 2006

Cancer

163

114

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“…Her2/neu overexpression is associated with a poor prognosis for breast, gastric, and ovarian cancer (4)(5)(6). On the basis of these characteristics, Her2/neu is an attractive therapeutic target.…”

Section: Introductionmentioning

confidence: 99%

Towards Sustained Silencing of HER2/neu in Cancer By Epigenetic Editing

Falahi

Huisman

Kazemier

et al. 2013

Molecular Cancer Research

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The human epidermal growth factor receptor-2 (HER2/neu/ERBB2) is overexpressed in several cancer types. Although therapies targeting the HER2/neu protein result in inhibition of cell proliferation, the anticancer effect might be further optimized by limiting HER2/neu expression at the DNA level. Towards this aim, epigenetic editing was performed to suppress HER2/neu expression by inducing epigenetic silencing marks on the HER2/neu promoter.HER2/neu expression and HER2/neu promoter epigenetic modification status were determined in a panel of ovarian and breast cancer cell lines. HER2/neu-overexpressing cancer cells were transduced to express a zinc finger protein (ZFP), targeting the HER2/neu gene, fused to histone methyltransferases (G9a, SUV39-H1)/super KRAB domain (SKD). Epigenetic assessment of the HER2/neu promoter showed that HER2/neu-ZFP fused to G9a efficiently induced the intended silencing histone methylation mark (H3K9me2). Importantly, H3K9me2 induction was associated with a dramatic downregulation of HER2/neu expression in HER2/neu-overexpressing cells. Downregulation by SKD, traditionally considered transient in nature, was associated with removal of the histone acetylation mark (H3ac). The downregulation of HER2/neu by induced H3K9 methylation and/or reduced H3 acetylation was sufficient to effectively inhibit cellular metabolic activity and clonogenicity. Furthermore, genome-wide analysis indicated preferential binding of the ZFP to its target sequence. These results not only show that H3K9 methylation can be induced but also that this epigenetic mark was instructive in promoting downregulation of HER2/neu expression.

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“…HER2 (erbB2) expression in ovarian cancer is associated with advanced stage, higher recurrence frequency, shorter survival time, and lower sensitivity to platinum-based chemotherapy (11,12). Trastuzumab and pertuzumab are humanized anti-HER2-targeted antibodies with different modes of action (13,14).…”

Section: Introductionmentioning

confidence: 99%

Trastuzumab and Pertuzumab Produce Changes in Morphology and Estrogen Receptor Signaling in Ovarian Cancer Xenografts Revealing New Treatment Strategies

Faratian

Zweemer

Nagumo

et al. 2011

Clinical Cancer Research

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Purpose: The aim of this study was to investigate the antitumor effects of HER2-directed combination therapy in ovarian cancer xenograft models to evaluate their potential. The combinations of trastuzumab and pertuzumab, and trastuzumab and aromatase inhibitor therapy were investigated.Experimental Design: The effects of trastuzumab, pertuzumab, and letrozole on growth response, apoptosis, morphology, and gene and protein expression were evaluated in the SKOV3 ovarian cancer cell line xenograft and a panel of five human ovarian xenografts derived directly from clinical specimens.Results: The combination of HER2-directed antibodies showed enhanced antitumor activity compared with single antibody therapy in the SKOV3 xenograft model. Apoptosis, morphology, and estrogenregulated gene expression were modulated by these antibodies in both spatial and temporal manners. A panel of ovarian cancer xenografts showed differential growth responses to the combination of trastuzumab and pertuzumab. High HER2 expression and increasing HER3 protein expression on treatment were associated with growth response. In trastuzumab-treated SKOV3 tumors, there was a change in tumor morphology, with a reduction in frequency of estrogen receptor alpha (ERa)-negative clear cell areas. Trastuzumab, but not pertuzumab, increased expression of ERa in SKOV3 xenografts when analyzed by quantitative immunofluorescence. ERa and downstream signaling targets were modulated by trastuzumab alone and in combination. Trastuzumab enhanced the responsiveness of SKOV3 xenografts to letrozole when given in combination.Conclusions: These data suggest that trastuzumab in combination with pertuzumab could be an effective approach in high HER2-expressing ovarian cancers and could also enhance sensitivity to endocrine therapy in ERa-positive ovarian cancer. Clin Cancer Res; 17(13); 4451-61. Ó2011 AACR.

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HER-2 overexpression is an independent marker of poor prognosis of advanced primary ovarian carcinoma: a multicenter study of the GINECO group

Abstract: HER-2 appeared to influence the outcome of advanced ovarian cancer patients included in a clinical trial with prolonged follow-up, thereby suggesting that HER-2 is a potential target for treatment of this cancer.

Cited by 96 publications

References 26 publications

Phosphorylated 4E binding protein 1: A hallmark of cell signaling that correlates with survival in ovarian cancer

Phosphorylated 4E binding protein 1: A hallmark of cell signaling that correlates with survival in ovarian cancer

Towards Sustained Silencing of HER2/neu in Cancer By Epigenetic Editing

Trastuzumab and Pertuzumab Produce Changes in Morphology and Estrogen Receptor Signaling in Ovarian Cancer Xenografts Revealing New Treatment Strategies

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