This dissertation focuses on the central hypothesis that in breast cancer cells containing the estrogen receptor-α (ER-α+) and wild-type p53, the BRCA-1 tumor suppressor gene is positively regulated by the steroid hormone estrogen and negatively regulated by Aromatic Hydrocarbon Receptor (AhR) ligands which damage DNA. In this dissertation, we demonstrate that BRCA-1 promoter activity is reduced by the DNA damaging agent Benzo[a]pyrene in breast cancer cells containing both a functional estrogen receptor and p53 pathway. In addition, our data suggests that exposure of MCF-7 breast cancer cells to estrogen stimulates transcription from the BRCA-1 5 ' flanking region, and this increase in transcription is paralleled by an increase in estrogen receptor-alpha interaction at the BRCA-1 promoter between -46 → -14 upstream of exon 1b. We report that in both untreated and estrogen-treated M CF-7 cells, a transcriptional complex, which we have termed an "Estrogen Responsive Unit" (ERU), containing AP-1, Sp1, and CREB family members, forms at the same -46 → -14 region which binds ER-α. Moreover, we show that wild-type p53 is required for estrogen induction of BRCA-1 and overexpression of a dominant-negative mutant variant of p53 can prevent this induction. Finally, we show that overexpression of wild-type p53 is able to disrupt the estrogen receptor interaction with the BRCA-1 ERU under both basal and estrogen-induced conditions while mutant p53 is only able to disrupt this interaction when estrogen is present. Taken together, these data suggest that loss of function of either the estrogen receptor-α or p53 signaling pathways may result in an inability for BRCA-1 regulation to occur and may in turn be a risk factor in the etiology of sporadic breast cancer.
| Identifer | oai:union.ndltd.org:arizona.edu/oai:arizona.openrepository.com:10150/280421 |
| Date | January 2003 |
| Creators | Jeffy, Brandon David |
| Contributors | Romagnolo, Donato F. |
| Publisher | The University of Arizona. |
| Source Sets | University of Arizona |
| Language | en_US |
| Detected Language | English |
| Type | text, Dissertation-Reproduction (electronic) |
| Rights | Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author. |
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