Expression of the epidermal growth factor system in endometrioid endometrial cancer

Ejskjær, Kirsten; Sørensen, Boe Sandahl; Poulsen, Steen Seier; Forman, Axel; Nexø, Ebba; Mogensen, Ole

doi:10.1016/j.ygyno.2006.07.015

Cited by 52 publications

(54 citation statements)

References 32 publications

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“…Overexpression of ERBB3 promotes tumorigenesis through multiple mechanisms including cell cycle progression, stimulation of cell migration, and invasion primarily via activation of the PI3K pathway (Sithanandam and Anderson 2008). ERBB3 is highly expressed in endometrial cancer, but the functional role remains unclear (Srinivasan et al 1999;Ejskjaer et al 2007). RPS6KC1 (encoding ribosomal protein S6 kinase polypeptide 1) is another potential oncogene.…”

Section: Discussionmentioning

confidence: 99%

Whole-exome sequencing combined with functional genomics reveals novel candidate driver cancer genes in endometrial cancer

et al. 2012

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Endometrial cancer is the most common gynecological malignancy, with more than 280,000 cases occurring annually worldwide. Although previous studies have identified important common somatic mutations in endometrial cancer, they have primarily focused on a small set of known cancer genes and have thus provided a limited view of the molecular basis underlying this disease. Here we have developed an integrated systems-biology approach to identifying novel cancer genes contributing to endometrial tumorigenesis. We first performed whole-exome sequencing on 13 endometrial cancers and matched normal samples, systematically identifying somatic alterations with high precision and sensitivity. We then combined bioinformatics prioritization with high-throughput screening (including both shRNA-mediated knockdown and expression of wild-type and mutant constructs) in a highly sensitive cell viability assay. Our results revealed 12 potential driver cancer genes including 10 tumor-suppressor candidates (ARID1A, INHBA, KMO, TTLL5, GRM8, IGFBP3, AKTIP, PHKA2, TRPS1, and WNT11) and two oncogene candidates (ERBB3 and RPS6KC1). The results in the ''sensor'' cell line were recapitulated by siRNA-mediated knockdown in endometrial cancer cell lines. Focusing on ARID1A, we integrated mutation profiles with functional proteomics in 222 endometrial cancer samples, demonstrating that ARID1A mutations frequently co-occur with mutations in the phosphatidylinositol 3-kinase (PI3K) pathway and are associated with PI3K pathway activation. siRNA knockdown in endometrial cancer cell lines increased AKT phosphorylation supporting ARID1A as a novel regulator of PI3K pathway activity. Our study presents the first unbiased view of somatic coding mutations in endometrial cancer and provides functional evidence for diverse driver genes and mutations in this disease.

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Section: Discussionmentioning

confidence: 99%

Whole-exome sequencing combined with functional genomics reveals novel candidate driver cancer genes in endometrial cancer

et al. 2012

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“…Earlier clinical studies in other disease entities show that potential markers of sensitivity to EGFR TKIs include the presence of EGFR gene amplification, mutations of the EGFR gene, and increased expression of EGFR ligands (Baselga and Arteaga, 2005). Earlier studies have demonstrated significantly higher expression levels of the EGFR ligands TGF-a and amphiregulin in EC compared with normal endometrium (Pfeiffer et al, 1997;Ejskjaer et al, 2007). The roles of EGFR gene amplification or mutations in EC, however, have not yet been studied.…”

Section: Discussionmentioning

confidence: 99%

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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“…Moreover, endometrial cancer demonstrated significantly higher expression levels of the EGFR ligands TGF-a and amphiregulin compared with normal endometrium (Pfeiffer et al, 1997;Ejskjaer et al, 2007). The central role of HER2 and EGFR in growth and differentiation of both normal and malignant cancer cells and their availability to extracellular manipulation make both HER2 and EGFR attractive targets for pharmacological intervention.…”

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confidence: 99%

Activity of lapatinib a novel HER2 and EGFR dual kinase inhibitor in human endometrial cancer cells

et al. 2008

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In this study, we explore the therapeutic potential of lapatinib a selective inhibitor of both the EGFR and HER2 tyrosine kinases for the treatment of endometrial cancer. The effect of lapatinib on tumour cell growth and receptor activation was studied in a panel of human endometrial cancer cell lines. Candidate molecular markers predicting sensitivity were assessed by baseline gene expression profiling, ELISA, and western blot analyses. Multiple drug effect/combination index (CI) isobologram analysis was used to study the interactions between chemotherapeutic drugs and lapatinib. Concentration-dependent anti-proliferative effects of lapatinib were seen in all endometrial cancer cell lines tested, but varied significantly between individual cell lines (IC 50 range: 0.052 -10.9 mmol). HER2 overexpression or increased expression of EGFR was significantly associated with in vitro sensitivity (P ¼ 0.024 or 0.011, respectively). Lapatinib exerts growth inhibition in a PTEN-independent manner. Sensitive cell lines also exhibited increased expression of EGFR ligands or HER3. In contrast, lapatinib-resistant cell lines exhibited high androgen receptor (AR) levels or epithelial-to-mesenchymal transition (post-EMT) features. In endometrial cancer cells, at a wide range of clinically achievable drug concentrations, additive and synergistic interactions were observed for lapatinib plus carboplatin, paclitaxel, docetaxel, and doxorubicin. These observations provide a clear biologic rational to test lapatinib as a single agent or in combination with chemotherapy in endometrial cancer with HER2 overexpression. Expression of EGFR, its ligands, HER3, AR, and post-EMT markers warrant further evaluation to help define patients with HER2-nonoverexpressing endometrial cancer most likely to benefit from lapatinib.

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Expression of the epidermal growth factor system in endometrioid endometrial cancer

Cited by 52 publications

References 32 publications

Whole-exome sequencing combined with functional genomics reveals novel candidate driver cancer genes in endometrial cancer

Whole-exome sequencing combined with functional genomics reveals novel candidate driver cancer genes in endometrial cancer

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

Activity of lapatinib a novel HER2 and EGFR dual kinase inhibitor in human endometrial cancer cells

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