Date of Award

12-2013

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Legacy Department

Biological Sciences

Advisor

Dr. Wen Y. Chen

Committee Member

Dr. Brian W. Booth

Committee Member

Dr. Andrew S. Mount

Committee Member

Dr. Charles D. Rice

Committee Member

Dr. T.R. Jeremy Tzeng

Abstract

Cancer stem cells (CSCs) are defined as a small population of tumor initiating cells that are responsible for the initiation, development, progression, and recurrence of cancer. The chemo and radiation resistance of CSCs remains one of the major obstacles in conventional anti-cancer therapies. One of the reasons that conventional chemotherapeutics are not effective in targeting CSCs is that CSCs are usually in a non-proliferative or dormant state. In this perspective, targeting CSCs by inducing its proliferation and differentiation and simultaneously applying chemotherapeutics may be an alternative approach. The current study investigates the effect of prolactin (PRL), a hormone intimately involved in mammary gland development, combined with cisplatin in targeting breast CSCs. We found that mammary gland CSCs treated with PRL undergo symmetric cell division with diminished ability to form tumorspheres. Moreover, the PRL and cisplatin combination treatment significantly inhibited secondary tumorsphere formation as compared to cisplatin alone, suggesting that PRL sensitized mammary gland CSCs to cisplatin. The IC50 value of cisplatin was cut by more than half with the addition of PRL in secondary tumorspheres formation assay. The effects of this combinational approach were further confirmed through tumor allograft growth in mice. The inhibitory effect was likely through the inhibition of the PI3K/AKT pathway. Furthermore, PRL and cisplatin combination treatment of mammary tumors in neu transgenic mice significantly delayed tumor growth and reduced tumorigenicity. Taken together, this study provided evidence that addition of PRL to conventional chemotherapy (cisplatin) may be an effective method to target breast CSCs.

Share

COinS