Research article

A functional Notch–survivin gene signature in basal breast cancer

Connie W Lee¹ , Karl Simin¹ , Qin Liu² , Janet Plescia¹ , Minakshi Guha¹ , Ashraf Khan³ , Chung-Cheng Hsieh¹ and Dario C Altieri¹

¹  Department of Cancer Biology and the Cancer Center, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA

²  Department of Medicine, Preventive and Behavioral Medicine, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA

³  Department of Pathology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA

author email corresponding author email

Breast Cancer Research 2008, 10:R97doi:10.1186/bcr2200

Published:	24 November 2008

Abstract

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.