Document Details

Document Type:   Dissertation
Title:   Effects of Progestins on the Expression of Manganese Superoxide Dismutase (MnSOD) and Activating Enhancer Protein-2 Gamma (AP-2gamma) in T47D Human Breast Cancer Cells
Author:   Aaron Keith Holley
College:   Joan C. Edwards School of Medicine
Degree Program:   Biomedical Sciences, Ph.D.
Degree:   Doctor of Philosophy
Committee Director:   Michael R. Moore
Document Availability:   Document available for World-Wide access.
Date of Defense:   04/08/2008

Progestins, a class of steroid hormones, play an important role in development of the breast and other tissues in women. They are often a component of hormone replacement therapy for post-menopausal women, and have been implicated in the development of breast cancer in patients that take this type of treatment. Identifying the genes that are regulated by progestins in breast cancer can lead to a better understanding of the mechanisms by which these hormones enhance cancer development, as well as the potential for improved therapies for this deadly disease. In the following dissertation study, manganese superoxide dismutase (MnSOD, a primary antioxidant enzyme) and activating enhancer protein 2- (AP-2, tumor suppressing transcription factor) were identified as two genes regulated by progestins in the progesterone receptor (PR)-rich T47D human breast cancer cell line. MnSOD was up-regulated by progestins in a time- and concentration-dependent manner at the protein, mRNA, and enzyme activity level. The effect was specific to progestins, occurred through the progesterone receptor, and was a secondary effect (dependent on new protein synthesis). Part of the mechanism of regulation was the activation of two distinct signal transduction pathways by progestins: the mitogen-activated protein kinase (MAPK) and protein kinase A (PKA) pathways. Physiological effects of MnSOD expression on progestin protection from cell death and stimulation of cell migration were studied, but the results were inconclusive. AP-2 was down-regulated by progestins in a time- and concentration-dependent manner at the protein and mRNA level. The effect was specific to progestins and occurred through the progesterone receptor. Progestin inhibition of AP-2 mRNA expression was a primary effect, independent of new protein synthesis. The simultaneous stimulation of MnSOD expression and down-regulation of AP-2 expression by progestins in T47D human breast cancer cells may be part of the larger effect of progestins on breast cancer cell proliferation and protection from cell death. These results add to the body of knowledge of the effects of steroid hormones on breast cancer, and may lead to new or improved therapies for this disease.  

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