A functional Notch-survivin gene signature in basal breast cancer.
BACKGROUND
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.
Lee
Connie W
CW
Department of Cancer Biology, Cancer Center, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA.
Simin
Karl
K
Liu
Qin
Q
Plescia
Janet
J
Guha
Minakshi
M
Khan
Ashraf
A
Hsieh
Chung-Cheng
CC
Altieri
Dario C
DC
D001943:Breast Neoplasms / Q000235:genetics*; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D020868:Gene Silencing; D006801:Humans; D007124:Immunoenzyme Techniques; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors / Q000235:genetics*; D011980:Receptors, Progesterone / Q000378:metabolism; D015398:Signal Transduction; D000077022:Survivin; D014162:Transfection
C107489:BIRC5 protein, human; D047628:Estrogen Receptor alpha; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D011980:Receptors, Progesterone; D000077022:Survivin