Link to the University of Pittsburgh Homepage
Link to the University Library System Homepage Link to the Contact Us Form

Roles of the Estrogen Receptors and the Nuclear Matrix in Breast Cancer Development and Tamoxifen Resistance

Sarachine, Miranda Jean (2009) Roles of the Estrogen Receptors and the Nuclear Matrix in Breast Cancer Development and Tamoxifen Resistance. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

Primary Text

Download (4MB) | Preview


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.


Social Networking:
Share |


Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Sarachine, Miranda
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairFreeman, Brucefreerad@pitt.eduFREERAD
Committee MemberDay, Billy Wbday@pitt.eduBDAY
Committee MemberRomero, Guillermoggr@pitt.eduGGR
Committee MemberLatimer,
Committee MemberConrads, Thomastpc7@pitt.eduTPC7
Date: 19 November 2009
Date Type: Completion
Defense Date: 10 September 2009
Approval Date: 19 November 2009
Submission Date: 5 November 2009
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Molecular Pharmacology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Breast Cancer; Tamoxifen; Proteomics; Ductal Carci
Other ID:, etd-11052009-142053
Date Deposited: 10 Nov 2011 20:04
Last Modified: 15 Nov 2016 13:51


Monthly Views for the past 3 years

Plum Analytics

Actions (login required)

View Item View Item