Breast cancer is an endocrine-responsive neoplasm which is primarily sensitive to the mitogenic effects of the steroid hormone estrogen. Estrogen exerts its effects by binding to the estrogen receptor (ER). As such, the presence or absence of ER in breast tumors is an important factor in the determination of the prognosis of the breast cancer patient, as well as in the determination of the treatment strategy used. The function of the wild type ER is well characterized, however little is known with regards to variant ERs in breast cancer. As a result, the presence of ER variants in human breast cancer has received much attention over the past several years, as researchers have endeavored to identify their function in the human breast. While ER variant proteins have yet to be identified in human breast tissue, tumor or otherwise, significant progress has been made towards the identification and characterization of ER mRNA variants. Studies have identified a plethora of variant ER transcripts, however the best characterized of these variant ER mRNAs may be those which lack either exon 5 or exon 7 Exon 5 and exon 7 both encode regions of the hormone binding domain of the ER, and the deletion of these exons putatively results in variant receptor proteins which are truncated within the hormone binding domain. Functional analyses of these variant proteins have shown that the exon 5 deletion variant ER is constitutively active, regulating the expression of estrogen-responsive genes. The exon 7 deletion variant ER is not able to regulate the transcription of estrogen-responsive genes, however it does function in a dominant-negative manner, inhibiting the actions of the wild type receptor when the two are coexpressed The research herein has employed a variety of approaches to characterize the expression patterns of wild type and exon 5 deletion variant ER mRNAs in human breast cancer cell lines and identify some of the consequences the expression of these variant ER transcripts has on the breast cancer cell. Growth studies indicate that MCF-7 human breast cancer cells which express an elevated percentage of the exon 5 deletion variant ER transcript proliferate at a faster rate, in the absence of estrogen, than those cells which express an elevated percentage of wild type ER transcript. MCF-7 cells which express an elevated percentage of the exon 5 deletion varian ER transcript are less responsive to the growth-stimulatory effects of estrogen than MCF-7 cells which express a higher percentage of wild type ER mRNA. The growth of MCF-7 stocks which express an elevated percentage of the wild type ER mRNA was significantly stimulated above control levels by day 3 of treatment, while the growth of MCF-7 cells which express an elevated percentage of the exon 5 deletion varian ER transcript were not significantly stimulated above control levels until day 7 of treatment. (Abstract shortened by UMI.) / acase@tulane.edu
| Identifer | oai:union.ndltd.org:TULANE/oai:http://digitallibrary.tulane.edu/:tulane_26286 |
| Date | January 1996 |
| Contributors | Klotz, Diane Michelle (Author), Hill, Steven M (Thesis advisor) |
| Publisher | Tulane University |
| Source Sets | Tulane University |
| Language | English |
| Detected Language | English |
| Rights | Access requires a license to the Dissertations and Theses (ProQuest) database., Copyright is in accordance with U.S. Copyright law |
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