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Identification of DNA sequence variants in the estrogen receptor pathway in breast cancer

Bahreini, Seyed Amir (2016) Identification of DNA sequence variants in the estrogen receptor pathway in breast cancer. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Breast cancer is of public health importance with an increasing incidence over the past decade. Estrogen Receptor (ER) activity is critical for promoting majority of breast cancers. Inhibiting ER is one of the most successful targeted therapies in oncology. Studies have suggested that genomic variation in ER binding sites and ESR1 gene may be responsible for endocrine treatment response and cancer progression. We investigated the role of single nucleotide variants (SNVs) in the ER pathway in breast cancer, including clinically relevant mutations in ER gene and regulatory variants in ER binding sites. First, we developed a computational pipeline to identify SNVs in ER binding sites, using chromatin immunoprecipitation-sequencing (ChIP-seq) data from hormone responsive breast cancer cells and tumors. Analysis of ER ChIP-seq data from multiple MCF7 studies characterized a SNV within intron 2 of the IGF1R gene, rs62022087, predicted to increase the affinity for ER binding. By integrating 43 ER ChIP-seq data sets, multi-omics and clinical data, we identified SNVs regulating downstream target genes which may contribute to patients’ survival. Second, we used sensitive detection methods to detect mutations and identified high frequencies ESR1 mutations in primary tumors, metastatic lesions and cell-free DNA samples. This result may be due to higher sensitivity of our study in detecting mutations at very low allele frequency. Finally, we generated appropriate knock-in cell lines through CRISPR technology to study ER mutations. RNA-seq studies revealed ER mutations are can activate estrogen regulated genes in a ligand independent manner and also may induce/repress a set of novel targets. Cell adhesion assays demonstrated mutants are less adhesive to Collagen I which may be a marker of metastasis. Taken together, our findings indicate that SNVs in ER pathway are clinically important and may predict drug response in ER+ breast cancer. From the public health perspective, screening for these impactful variants will be soon part of the genetic testing as our knowledge of genome improves. This will eventually help initiatives to reduce public health burden by choosing the right treatment for breast cancer patients in personalized manner.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Bahreini, Seyed Amirseb108@pitt.eduSEB108
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairOesterreich, Steffisto16@pitt.eduSTO16
Committee MemberKammerer, Candace Mcmk3@pitt.eduCMK3
Committee MemberLee, Adrian V.avl10@pitt.eduAVL10
Committee MemberMinster, Ryan Leerminster@pitt.eduRMINSTER
Date: 29 June 2016
Date Type: Publication
Defense Date: 6 April 2016
Approval Date: 29 June 2016
Submission Date: 31 March 2016
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 175
Institution: University of Pittsburgh
Schools and Programs: School of Public Health > Human Genetics
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Breast cancer, genetics, single nucleotide variants, estrogen receptor, regulatory variants, endocrine resistance, metastasis, circulating free DNA
Date Deposited: 29 Jun 2016 17:29
Last Modified: 01 May 2018 05:15


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