Epidermal growth factor receptor activation in prostate cancer by three novel missense mutations

Metastasis is the chief cause of mortality from cancer, but the mechanisms leading to metastasis are poorly understood. We used a proteomics approach to screen for metastasis-associated proteins and found that collapsin response mediator protein-4 (CRMP4) expression was inversely associated with the lymph node metastasis of prostate cancer (PCa). Subsequent in vitro and in vivo studies revealed that overexpression of CRMP4 not only suppressed the invasion ability of PCa cells, but also strongly inhibited tumor metastasis in an animal model. Furthermore, methylation of a CpG island within the promoter region of the CRMP4 gene is responsible for downregulation of CRMP4 expression. Thus, in this study, we show new function of CRMP4 as a metastasissuppressor in PCa. The findings provide new mechanistic insights into metastasis and therapeutic potential for this most common male cancer.

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“…The mock transfected cells were used as a control (Cai et al, 2008). Similar data were obtained from at least three independent experiments.…”

Section: Matrigel Invasion Assaymentioning

confidence: 53%

Expression profiling identifies new function of collapsin response mediator protein 4 as a metastasis-suppressor in prostate cancer

Gao

Pang

et al. 2010

Oncogene

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“…Interestingly, the samples analyzed belonged to Caucasian, African American and Korean patients, and three of the four mutated adenocarcinomas were from Korean patients. Later on, Cai et al 33 reported that three of these four mutations were constitutively active oncogenic mutations. Schlomm et al 13 also analyzed the EGFR exons 18-21, but did not find mutations, although the number of adenocarcinomas analyzed was very low.…”

Section: Discussionmentioning

confidence: 99%

Molecular alterations of EGFR and PTEN in prostate cancer: association with high-grade and advanced-stage carcinomas

et al. 2010

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Prostate cancer is the second cause of cancer-related death in men of the Western world. The potential prognostic role of the combined alterations in EGFR and PTEN in prostate cancer is not well established. It was the aim of the study to investigate this role. Prevalence of EGFR and PTEN somatic mutations, EGFR amplification and EGFR protein expression were investigated in a series of prostate adenocarcinomas, classified according to the current Gleason grading system. Mutational analysis revealed eight EGFR and three PTEN mutations in 98 (8%) and 92 (3%) prostate adenocarcinomas, respectively. The combined prevalence of EGFR-PTEN mutations was 11%. EGFR overexpression was present in 31% of adenocarcinomas, with a marginally significant difference (P ¼ 0.068) between Gleason grade r7 adenocarcinomas and Gleason grade Z8 and metastatic adenocarcinomas. Four cases (4 of 31; 13%) had an EGFR gene gain due to chromosome 7 polysomy. In 35% of adenocarcinomas we found some type of EGFR-PTEN alteration, with a tendency to be associated with advanced-stage prostate adenocarcinomas (P ¼ 0.04). The IVS18 þ 19 polymorphism was also associated with more advanced prostate adenocarcinomas. This is the first study reporting mutations of EGFR and PTEN in the same series of prostate adenocarcinomas. Protein overexpression is the most frequent EGFR abnormality. Mutations in EGFR and PTEN genes are a minor event, although prostate cancer represents the third neoplasm in which the EGFR gene mutations are more prevalent. Alterations in the EGFR-PTEN signaling pathway are present in a third of prostate adenocarcinomas, particularly affecting the more advanced cases. Keywords: EGFR; PTEN; mutation; overexpression; FISH; prostate cancer EGFR belongs to the ErbB family of tyrosine kinase receptors.1 They are activated by binding to peptide growth factors of the EGF family, leading to activation of multiple downstream pathways. The Ras-Raf-MEK-ERK1/2, STAT-3, and STAT-5, and the PI3K/PTEN-Akt-Mtor cascades are the main pathways activated downstream of ErbB receptors, which have strong regulatory effects on cell proliferation, differentiation, survival and migration. 2,3 In many different cancer cell types, the ErbB pathway becomes hyperactivated by a range of mechanisms.2,4

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“…The EGFR gene encompasses 118 kb of sequence on the short arm of human chromosome 7 and contains 28 exons, which encode 1186 amino acids (1). The EGFR protein can be divided into three domains: an extracellular ligand binding domain, a transmembrane domain and an intracellular domain.…”

Section: Introductionmentioning

confidence: 99%

Structural analysis of the EGFR TK domain and potential implications for EGFR targeted therapy

et al. 2012

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Abstract. The development and clinical application of TK domain inhibitors (TKIs) provide important insights into the broader field of cancer-targeted therapies. To discuss the recent advances in the atomic level understanding of EGFR TK domain mutations, we aim at highlighting the current and future importance of these studies on malignancies where the TK domain is improperly activated. The analysis is conducted on published TK domain crystal structures deposited in the Protein Data Bank, or homology structures generated by homology modeling and AutoDock 4.2 software using the program O. Mutations in exon 19 are the most common pathogenic mutations, so the crystal structures with these mutations are analyzed and compared in detail. In addition, we demonstrate how these crystal structures of EGFR conformation with TK domain mutations and those binding with small molecule inhibitors unveil the active or inactive mechanisms. As to the increasing resistance to the TKI, we summarize the progress on overcoming this challenge. Simultaneously, we predict the structure of BIKW-2992 binding to EGFR and compare it with the validated structure of HKI-272. It is hoped that a more accurate resistance mechanism would be found. In brief, we believe that this research will provide insights into EGFR targeted therapies.

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Epidermal growth factor receptor activation in prostate cancer by three novel missense mutations

Cited by 40 publications

References 33 publications

Expression profiling identifies new function of collapsin response mediator protein 4 as a metastasis-suppressor in prostate cancer

Expression profiling identifies new function of collapsin response mediator protein 4 as a metastasis-suppressor in prostate cancer

Molecular alterations of EGFR and PTEN in prostate cancer: association with high-grade and advanced-stage carcinomas

Structural analysis of the EGFR TK domain and potential implications for EGFR targeted therapy

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