A functional Notch–survivin gene signature in basal breast cancerReport as inadecuate




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Breast Cancer Research

, 10:R97

First Online: 24 November 2008Received: 21 July 2008Revised: 12 November 2008Accepted: 24 November 2008

Abstract

IntroductionBasal-type, or triple-negative, breast cancer lacking estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2 expression is a high-risk disease for which no molecular therapies are currently available. We studied genetic signatures of basal breast cancer potentially suitable for therapeutic intervention.

MethodsWe analyzed protein expression of the Notch-1 intracellular domain and survivin by immunohistochemistry in a series of basal breast cancer patients. A hierarchical clustering and overall survival analysis was carried out on a microarray mRNA database of 232 breast cancer patients. Fifteen published mRNA datasets containing estrogen receptor-negative or estrogen receptor-positive samples were subjected to meta-analysis for co-segregated gene expression. Experiments of plasmid transfection and gene silencing were carried out in estrogen receptor-negative MDA-MB-231 breast cancer cells.

ResultsThe developmental signaling regulator Notch-1 was highly expressed in breast cancer, compared with normal tissue, and was segregated with basal disease. Higher Notch-1 levels correlated with progressively abbreviated overall survival, and with increased expression of survivin, a tumor-associated cell death and mitotic regulator implicated in stem cell viability. Analysis of Pearson-s correlation coefficient indicated that Notch-1 and survivin co-segregated in basal breast cancer. Notch-1 stimulation in MDA-MB-231 cells increased survivin expression, whereas silencing Notch reduced survivin levels.

ConclusionsA Notch-1–survivin functional gene signature is a hallmark of basal breast cancer, and may contribute to disease pathogenesis. Antagonists of Notch and survivin currently in the clinic may be tested as novel molecular therapy for these recurrence-prone patients.

AbbreviationsERestrogen receptor

HER-2human epidermal growth factor receptor 2

NICNotch-1 intracellular domain

PBSphosphate-buffered saline

siRNAsmall interfering RNA.

Electronic supplementary materialThe online version of this article doi:10.1186-bcr2200 contains supplementary material, which is available to authorized users.

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Author: Connie W Lee - Karl Simin - Qin Liu - Janet Plescia - Minakshi Guha - Ashraf Khan - Chung-Cheng Hsieh - Dario C Altieri

Source: https://link.springer.com/







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