UMMS Affiliation

Department of Cancer Biology; Department of Pathology

Publication Date

2008-11-26

Document Type

Article

Subjects

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

Disciplines

Cancer Biology | Life Sciences | Medicine and Health Sciences

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.

DOI of Published Version

10.1186/bcr2200

Source

Breast Cancer Res. 2008;10(6):R97. Epub 2008 Nov 24. Link to article on publisher's site

Journal/Book/Conference Title

Breast cancer research : BCR

Comments

Co-author Minakshi Guha is a student in the Cancer Biology program in the Graduate School of Biomedical Sciences (GSBS) at UMass Medical School.

Related Resources

Link to Article in PubMed

PubMed ID

19025652

Download

Share

COinS