Date of Award

Fall 2011

Degree Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

Department

Biochemistry

Supervisor

John Hassell

Co-Supervisor

Karen Mossman

Language

English

Committee Member

Karen Mossman

Abstract

The cancer stem cell hypothesis claims that only a small subpopulation of cells within a tumor is responsible for tumor growth, recurrence after treatment and metastasis. These cells have been termed tumor-initiating cells or cancer stem cells and are functionally defined by their capacity to elicit the growth of tumors in immune-compromised animals that recapitulate the cellularity of the tumor from which they were isolated. Several reports demonstrate that tumor-initiating cells are resistant to most current treatments. Hence, novel therapies for breast cancer should be developed that specifically target these tumorigenic cells. The Notch signaling pathway is hyperactive in human breast cancer as well as in mouse mammary tumor-initiating cells. In this study, I have found that inhibitors of the pathway target breast tumor-initiating cells from various breast cancer subtypes and may provide a novel therapy for breast cancer. MRK-003, a gamma-secretase inhibitor that blocks Notch signaling, inhibited the self-renewal of breast tumor-initiating cells in vitro and reduced tumor growth in xenograft models. MRK-003 inhibited proliferation of tumor cells within xenografts and induced their apoptosis and differentiation towards the myoepithelial lineage. Expression of the Notch pathway antagonists led to similar outcome in human breast tumor cell lines. Notably, tumors in MRK-003 treated mice were devoid of tumor initiating cells, suggesting that inhibitors of Notch signaling may lead to durable cancer cures. These findings suggest that GSIs target breast tumor-initiating cells and may prove to be effective novel anti breast cancer drugs.

McMaster University Library

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