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Targeting estrogen receptor as a strategy for personalized medicine in ovarian cancer

Andersen, Courtney (2016) Targeting estrogen receptor as a strategy for personalized medicine in ovarian cancer. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Ovarian cancer comprises a diverse set of diseases that are difficult to detect and treat successfully. Improving outcomes for ovarian cancer patients is contingent upon identifying targeted, individualized therapeutic strategies. One promising but under-utilized target is estrogen receptor-alpha (ER). ER is expressed in ~70% of epithelial ovarian cancers and epidemiologic studies implicate a role for estrogen in ovarian tumorigenesis. Further, clinical data suggest that a subset of ovarian cancer patients benefit from endocrine therapy. We hypothesized that ER drives development and progression of a subset of ovarian tumors and that outputs of ER function would identify patients who respond to endocrine therapy. We assessed endocrine response and mechanisms of ER signaling in models and clinical samples of high-grade serous ovarian cancer (HGSOC). These studies suggested that expression of ER target genes (ERTGs) reflect active ER in HGSOC and correspond with endocrine responsiveness. In light of this, we profiled ERTG expression to evaluate changes in ER signaling during the progression from benign endometriosis to endometriosis-associated cancer (EAOC). This analysis suggested that canonical ER signaling becomes largely inactivated during this transformation and that de-repressed genes (e.g. FGF18, ESR2) may contribute to the evolution of EAOC. Finally, we compared ER and ERTG expression between serous and mucinous low malignant potential (LMP) tumors. Serous LMP tumors have high expression of ER and several ERTGs (e.g. GREB1). Taken together, our findings describe biomarkers that could identify ovarian cancer patients across multiple disease subtypes who would benefit clinically from endocrine therapy.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Andersen, Courtneyandersenc@upmc.eduCLA480000-0003-2064-2273
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairDeFranco, Dondod1@pitt.eduDOD1
Committee MemberLee, Adrianleeav@upmc.eduAVL10
Committee MemberVlad, Andaavlad@mwri.magee.eduANVST12
Committee MemberEdwards, Robertedwarp@mail.magee.eduRPE1
Thesis AdvisorOesterreich, Steffioesterreichs@upmc.eduSTO16
Date: 20 May 2016
Date Type: Publication
Defense Date: 16 February 2016
Approval Date: 20 May 2016
Submission Date: 29 March 2016
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Number of Pages: 167
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Pharmacology and Chemical Biology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: ovarian cancer, estrogen receptor, endocrine response, endocrine therapy, personalized medicine, fulvestrant, tamoxifen, predictive biomarkers, endometriosis, gynecologic oncology
Date Deposited: 20 May 2016 15:08
Last Modified: 15 Nov 2016 14:32
URI: http://d-scholarship.pitt.edu/id/eprint/27376

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