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GENETIC ALTERATIONS IN NUCLEAR RECEPTOR COACTIVATORS IN
BREAST CANCER
by
Anamaria Ioan Munteanu
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(PATHOBIOLOGY)
August 2010
Copyright 2010 Anamaria Ioan Munteanu
Object Description
| Title | Genetic alterations in nuclear receptor coactivators in breast cancer |
| Author | Ioan Munteanu, Anamaria |
| Author email | ioan@usc.edu; anamariaioan@gmail.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Pathobiology |
| School | Keck School of Medicine |
| Date defended/completed | 2010-05-24 |
| Date submitted | 2010 |
| Restricted until | Restricted until 05 Feb. 2011. |
| Date published | 2011-02-05 |
| Advisor (committee chair) | Press, Michael F. |
| Advisor (committee member) |
Stallcup, Michael R. Epstein, Alan L. Haiman, Christopher A. |
| Abstract | Steroid hormones play an important role in the development of breast cancer. Genetic alterations involving hormone receptor coactivator genes in breast cancer cells may influence tumor development by altering patterns of transcriptional activation or repression of target genes in hormone pathways. These alterations might cause changes in gene expression of key proteins involved in cellular homeostasis initiating proliferative changes providing a survival, growth, or expansion advantage for the cells containing the alterations.; Snap-frozen samples of breast cancer were analyzed for sequence alterations in coactivator genes involved in the estrogen receptor pathway (NCOA1, NCOA2, NCOA3, NCOA5, NCOA6, FLII, ZNF282, CARM1, and CALCOCO1). Sequence alterations were characterized as somatic mutations (SM), polymorphisms (SNPs), or short tandem repeat variations. Paraffin-embedded samples were used to assess gene copy number in coactivator genes located on chromosome 20q (NCOA3 NCOA5 and NCOA6), a region known to be amplified in breast cancer. The study population was comprised of 115 African-American, Latina, Asian, and Caucasian women diagnosed with breast cancer. A Fisher exact test was used to evaluate the correlation between the presence of genetic alterations and clinical and pathological patient characteristics as well as tumor biomarkers.; Somatic mutations were identified in three genes (3/9), non-synonymous SNPs were identified in seven genes (7/9), short tandem repeat variations were identified in two genes (2/2) and amplifications were identified in three genes (3/3). Somatic mutations were located in the C-terminal regions of NCOA3, NCOA6 and FLII genes of four different breast cancers (4/115, 3.5%). There were no significant correlations between these mutations and the factors considered in the analysis.; Non-synonymous SNPs were present at 33 different locations in 69 cases, synonymous SNPs were identified at 36 locations in 97 cases and short tandem repeat variations were identified in the polyglutamine region of NCOA3 or NCOA6 genes in 72 tumors. There were significant correlations detected between specific SNPs identified in the sequences of coactivator genes and patient ethnicity.; Polyglutamine region alterations were identified in NCOA3 and NCOA6. There were significant correlations between the specific genotypes of NCOA3 polyglutamine repeats with age at diagnosis and the presence or absence of lymph node metastasis in these patients.; Increased copy number was identified in 31 samples (31/115, 27%) in one or more of three genes: NCOA3, NCOA5 and NCOA6 and coamplification of all three genes was identified in 12 samples. The presence of increased gene copy number in these coactivators was correlated with HER2 amplification.; Nuclear receptor coactivators were relatively conserved. Few alterations were identified in the coding sequences and amplification status of the studied genes in breast cancers. The novel somatic mutations were found in functionally important regions of these genes and might have significant functional influence on the encoded protein, in breast epithelial cells. |
| Keyword | somatic mutation; SNP; FISH; gene amplification; nuclear receptor coactivator; breast cancer |
| Geographic subject (country) | USA |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m3279 |
| Contributing entity | University of Southern California |
| Rights | Ioan Munteanu, Anamaria |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | cisadmin@dots.usc.edu |
| Filename | etd-Ioan-3900 |
| Archival file | uscthesesreloadpub_Volume32/etd-Ioan-3900.pdf |
Description
| Title | Page 1 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@dots.usc.edu |
| Full text | GENETIC ALTERATIONS IN NUCLEAR RECEPTOR COACTIVATORS IN BREAST CANCER by Anamaria Ioan Munteanu A Dissertation Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (PATHOBIOLOGY) August 2010 Copyright 2010 Anamaria Ioan Munteanu |
