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A functional Notch–survivin gene signature in basal breast cancer

DOI: 10.1186/bcr2200

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Abstract:

We 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.The 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.A 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.The introduction of molecular gene signatures in breast cancer provides important prognostic and predictive information [1-3], and holds promise for individualized molecular therapy of these patients [4]. Certain subtypes of breast cancer, however, continue to pose therapeutic challenges [4]. For example, basal breast cancer is a myoepithelial disease variant characterized by high histologic grade [5], by the absence of HER-2 (ErB2) and receptors for estrogen and progesterone [6], by the expression of basal cytokeratins (that is, keratin

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