Department of Cancer Biology; Department of Pathology
Breast Neoplasms; Estrogen Receptor alpha; Female; *Gene Expression Profiling; Gene Silencing; Humans; Immunoenzyme Techniques; Microtubule-Associated Proteins; Middle Aged; Oligonucleotide Array Sequence Analysis; Receptor, Notch1; Receptors, Progesterone; Signal Transduction; Transfection
Cancer Biology | Life Sciences | Medicine and Health Sciences
INTRODUCTION: Basal-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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
Rights and Permissions
Citation: Breast Cancer Res. 2008;10(6):R97. Epub 2008 Nov 24. Link to article on publisher's site