All ETDs from UAB

Advisory Committee Chair

Trygve O Tollefsbol

Advisory Committee Members

Robert A Angus

Asim K Bej

Shahid M Mukhtar

Rosa A Serra

Document Type

Dissertation

Date of Award

2016

Degree Name by School

Doctor of Philosophy (PhD) College of Arts and Sciences

Abstract

For each regulatory pathway implementing environmental or internal messages, there is at least one additional pathway to relay a message to override or modify the original message, in the event of new or conflicting input. The opposing pathway may also be an instrument for negative feedback or redundancy as well as for transmission of additional encountered conditions or considerations. Because the multiple disease conditions based on aberrant cell cycle proliferation often require a level of correction independent of opposing feedback, selection of opposing pathways for complementary joint input is a practical approach to cancer and related proliferation-associated diseases. Accordingly, I tested the effects of raloxifene to up-regulate the TGF-beta pathway in combination with PX-866 to down-regulate the PI3K/Akt pathway in estrogen receptor expressing MCF-7 breast cancer cells. I evaluated upstream and downstream effects that led to decreased cell cycle proliferation, including expression and protein modification differences for well-studied regulatory genes and proteins such as hTERT, Cyclin D1, Cyclin E2 and Rb. In the process, the potential importance of newly emerging regulators was also disclosed in contribution to a better understanding of the complex cell cycle regulatory network. The indicated contributions of raloxifene and PX-866 alone and, especially, in combination provided proof of concept as well as a novel option for cancer treatment or prevention.

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