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Expression of HER-2 in MCF-7 breast cancer cells modulates anti-apoptotic proteins Survivin and Bcl-2 via the extracellular signal-related kinase (ERK) and phosphoinositide-3 kinase (PI3K) signalling pathways.
Siddiqa, Aisha; Long, Linda M; Li, Liuxia; Marciniak, Robert A; Kazhdan, Irene.
Afiliação
  • Siddiqa A; Department of Medicine, University of Texas Health Science Center, San Antonio, TX 78229, USA. siddiqa@uthscsa.edu
BMC Cancer ; 8: 129, 2008 May 02.
Article em En | MEDLINE | ID: mdl-18454859
BACKGROUND: The oncoprotein HER-2 is over-expressed and/or has undergone gene amplification in between 20 to 30% of breast and ovarian cancers. HER-2 amplified breast cancer is associated with a poor prognosis and increased resistance to chemo- and hormonal therapy. Data supporting the transforming potential of HER-2 are irrefutable but the mechanism by which HER-2 contributes to this process is complex and a unified model of HER2-induced increased cell proliferation and survival has not emerged.To understand the initial event(s) that take place by HER-2 over expression, we studied the effect of short term induction of HER-2 expression in the MCF7 breast cancer cell line. METHODS: We examined the modulation of apoptotic pathways by tetracycline-regulated HER-2 expression for 48 hrs in the MCF7 breast cancer cell line. Specific inhibitors were used to determine signalling pathways that are required for HER-2 induced up-regulation of survivin. RESULTS: Tetracycline regulated short term over expression of HER-2 in the MCF7 cell line increased the antiapoptotic proteins Bcl-2 and survivin levels. Significant increase of extracellular signal-related kinase (ERK) activation but not AKT1, AKT2 and STAT3 was observed in HER-2 over-expressing MCF7 cells. Specific inhibitors of ERK, and phosphoinositide-3 kinase (PI3K), inhibited the HER-2 induced up-regulation of survivin. We did not observe a change in survivin and NF-kappaB promoter activity in HER-2 expressing MCF7 cells. CONCLUSION: Our results indicate that short term over expression of HER-2 up regulates antiapoptotic proteins Bcl-2 and survivin in MCF7 cells. We determined that survivin is up-regulated via ERK activation and PI3K signalling. Additionally we show that survivin up-regulation is not at transcriptional level. These data provide insight into the mechanism(s) by which induction of HER-2 over expression up-regulates survivin and Bcl-2 and identifies new targets for therapy of breast cancer.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias da Mama / Regulação Neoplásica da Expressão Gênica / Receptor ErbB-2 / Proteínas Proto-Oncogênicas c-bcl-2 / Sistema de Sinalização das MAP Quinases / Proteínas Associadas aos Microtúbulos / Proteínas de Neoplasias Limite: Humans Idioma: En Revista: BMC Cancer Assunto da revista: NEOPLASIAS Ano de publicação: 2008 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias da Mama / Regulação Neoplásica da Expressão Gênica / Receptor ErbB-2 / Proteínas Proto-Oncogênicas c-bcl-2 / Sistema de Sinalização das MAP Quinases / Proteínas Associadas aos Microtúbulos / Proteínas de Neoplasias Limite: Humans Idioma: En Revista: BMC Cancer Assunto da revista: NEOPLASIAS Ano de publicação: 2008 Tipo de documento: Article País de afiliação: Estados Unidos