Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Anatomy and Cell Biology

Supervisor

Dr. Alison Allan

Abstract

Breast cancer is a leading cause of death in women, due primarily to ineffective treatment of metastatic disease. Despite being a lethal process, metastasis is surprisingly inefficient, with less than 0.5% of cancer cells able to successfully navigate the metastatic cascade, indicating that only a small proportion of cancer cells possess the necessary characteristics to establish metastases. Cancer stem cells (CSCs) have recently been identified in leukemia and solid tumors; however, the role of CSCs in breast cancer metastasis and therapy resistance remains poorly understood. Sub-populations of cells demonstrating stem-cell like characteristics (high expression of CSC markers and/or high ALDH activity, an enzyme involved in stem cell self-protection) were identified in MDA-MB-435, MDA-MB-231, MDA-MB-468 breast cancer cells, but not in MCF-7 cells. When isolated and compared to ALDHlowCD44- cells, ALDHhiCD44+ cells demonstrated increased metastatic behaviours in vitro. Furthermore, following injection into immunocompromised mice, ALDHhiCD44+ cells showed enhanced tumorigenicity and metastasis compared to ALDHlowCD44- cells, indicating that stem-like ALDHhiCD44+ cells may be important mediators of breast cancer metastasis. ALDHhiCD44+ cells from MDA-MB-231 and MDA-MB-468 cells that were exposed to chemotherapy or radiotherapy also demonstrated significantly increased cell survival relative to ALDHlowCD44- cells, potentially through an ALDH1-dependent manner. ALDH1 expression has previously been correlated with poor patient outcome and incidence of metastatic disease. To test a potential functional role for ALDH1 expression in metastasis and therapy resistance, the ALDH1 isozymes ALDH1A1 or ALDH1A3 were knocked down using siRNA in MDA-MB-468 and SUM159 breast cancer cell lines. ALDH1A1low cells demonstrated decreased metastatic abilities in vitro and in vivo; whereas ALDH1A3low cells demonstrated minimal changes in metastatic abilities in vitro but showed a significant reduction in metastatic capacity in vivo. Additionally, ALDH1A1low cells but not ALDH1A3low cells demonstrated increased sensitivity to both chemotherapy and radiation. Collectively, these data suggest that ALDH1 expression demonstrates a functional role in breast cancer metastasis and therapy resistance. Thus, drug development that targets ALDH1-expressing tumor cells may represent a novel therapeutic strategy to treat metastatic breast cancer patients in the future.


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