All ETDs from UAB

Advisory Committee Chair

Selvarangan Ponnazhagan

Advisory Committee Members

Stephen Watts

Jessy Deshane

Document Type

Thesis

Date of Award

2014

Degree Name by School

Master of Science (MS) College of Arts and Sciences

Abstract

Breast cancer stem cells (BCa-SC) are considered as a rare population of cells which cause resistance to chemotherapy in breast cancer (BCa). This population is characterized in humans and mice by CD24- CD44+ ALDH1+ phenotype and expresses mesenchymal properties that differ from the normal epithelial CD24+ CD44+ phenotype expressed in the majority of BCa cells. It has been widely accepted that tumor growth is sustained by BCa-SC that are similar to normal stem cells in which they have the ability to self-renew and differentiate. However, unlike their normal counterparts, BCa-SC are rare cells within tumors with the ability to self-renew and give rise to the phenotypically diverse tumor cell population to drive tumorigenesis instead of organogenesis like normal stem cells. Based on the pleomorphic properties of BCa-SC within the growing tumor, the present study investigated the plasticity of BCa-SC in vitro and in vivo using murine and human BCa cell lines. Results of this study demonstrated that specific changes in the expression of BCa-SC phenotype support a possible reprogramming of these cells based on cell cycle regulation. Since the presence of BCa-SC markers are key factors in promoting resistance to treatments, and based on our preliminary findings regarding tumor progression and growth kinetics of BCa-SC, we hypothesized that the use of cell cycle inhibitors in combination with chemotherapy drugs may serve as an effective treatment regimen to reduce BCa resistance. We examined the growth kinetics of BCa-SC primarily in vitro to determine the expression of phenotypic markers CD24, CD44, and expression levels of ALDH1 based on cell cycle regulation utilizing the murine BCa cell line 4T1 and human BCa cell lines MCF-7 and MDA-MB 231. Results of the present study identified an interesting modulation of the markers during specific time points which suggested a phenotypic reversion from the BCa-SC phenotype to the non-cancer stem cell (NCSC) phenotype. In an attempt to develop new therapies for BCa, we investigated the phenotypic reversion between the two populations of BCa (SC and NCSC) using cell cycle inhibitors including lovastatin and thymidine to block BCa-SC in the G1 and S phase of the cycle, respectively. Arresting these cells during the NCSC phenotype blocked the reversion back to the BCa-SC phenotype at later time points. These findings support our hypothesis that use of cell cycle inhibitors to arrest cells during the NCSC phenotype may serve as a better treatment-option. Developing a combination therapy with cell cycle inhibitor drugs may improve current therapeutic approaches and induce apoptosis in BCa-SC at specific stages of cell cycle while they do not exhibit BCa-SC characteristics. This may bring the field one step closer to designing effective therapies that may eliminate cancer and reduce the rate of relapse.

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