In the United States in 2009, 192,370 women are expected to be diagnosed with invasive breast cancer, and 62,280 with in situ disease. About 70% of these cases are estrogen receptor positive (ER+). There are two isoforms of the ER, α and β, that differ somewhat in structure and action. ERβ expression plays a protective role in breast cancer, and selective targeting of this isoform would have many beneficial effects. Tamoxifen has long been the standard of care for patients with ER+ breast cancer. A major problem with tamoxifen is the development of drug resistance. One of the mechanisms proposed for the development of tamoxifen resistance involves the loss of ERβ expression.
The first objective of this study was to screen a library of biphenyl C-cyclopropylalkylamides for their ability to function as ERβ-selective ligands. Two compounds were identified with modest selectivity for ERβ and anti-proliferative effects in breast cancer cells where they inhibited expression of c-Myc.
The nuclear matrix (NM), the structural scaffolding of the nucleus, plays a major role in many fundamental processes of the cell. Using the ER+ breast cancer cell line MCF-7 and an antiestrogen resistant derivative, along with subtype selective ER ligands, alterations in the abundance of specific proteins present in the NM were identified using a mass spectrometry (MS)-based relative quantitative methodology. Some of the most interesting proteins with altered abundance are NuMA, serpin H1, hnRNP R, and dynein heavy chain 5. These proteins may represent putative biomarkers to customize treatment. The alterations also provide a mechanistic understanding of tamoxifen resistance.
The NM was also investigated by MS in the earliest stage of breast cancer, ductal carcinoma in situ (DCIS), utilizing novel cell lines derived from normal (breast reduction), DCIS, and non-diseased contralateral breast surgical specimens. Two of the interesting proteins found to be altered in DCIS were HSP90 and EEF1D. These studies may provide biomarkers to aid in the diagnosis and treatment of breast cancer. In addition by understanding the mechanism behind the development of breast cancer, prevention becomes a possibility.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-11052009-142053 |
| Date | 19 November 2009 |
| Creators | Sarachine, Miranda Jean |
| Contributors | Billy W. Day, Ph.D., Bruce Freeman, Ph.D., Jean Latimer, Ph.D., Thomas Conrads, Ph.D., Guillermo Romero, Ph.D. |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-11052009-142053/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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