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FGFR4 OVEREXPRESSION AND HOTSPOT MUTATIONS ARE DRUGGABLE TARGETS FOR ENDOCRINE-RESISTANT LOBULAR BREAST CANCER

Levine, Kevin (2019) FGFR4 OVEREXPRESSION AND HOTSPOT MUTATIONS ARE DRUGGABLE TARGETS FOR ENDOCRINE-RESISTANT LOBULAR BREAST CANCER. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Invasive lobular carcinoma (ILC) is an understudied subtype of breast cancer that requires novel therapies in the advanced setting. Because most ILC tumors are estrogen receptor positive (ER+), first-line therapies for patients with ILC often include drugs that block estrogen signaling. Although these treatments have a high rate of initial success, de novo and acquired resistance remain major clinical problems. To study the mechanisms of resistance to endocrine therapy in ILC, we performed several transcriptomic studies. First, RNA-Sequencing of cell line models identified overexpression of fibroblast growth factor receptor 4 (FGFR4) as a top druggable target for estrogen-independent ILC. To test the clinical relevance of this finding, we next profiled treatment-naive primary ER+ ILC tumors. In this setting, elevated FGFR4 expression was poorly prognostic for distant recurrences, suggesting that FGFR4 may play a role in de novo resistance to endocrine therapy. To study acquired resistance, we next sequenced matched, metachronous primary and metastatic tumors. This study showed that FGFR4 expression increases dramatically in distant metastases of ER+ ILC treated with endocrine therapy. With recent publication of mutational profiles of metastatic breast cancer, we next queried datasets for DNA-level FGFR4 alterations. We found FGFR4 hotspot mutations were uniquely enriched in metastatic ILC, suggesting a multimodal selection of FGFR4 activation in advanced lobular carcinoma. Because of the consistent results pointing to FGFR4 as a key mediator of resistance in ILC, we next tested the effects of FGFR4 inhibition in vitro. Although blockade of FGFR4 had minimal effects on short-term growth, FGFR4 inhibition via shRNA or small molecules drastically decreased colony formation. Initial results from signaling studies show minimal effects of FGFR4 inhibition on estrogen signaling and cell cycle progression. Lastly, FGFR4 overexpression was not sufficient to drive in vitro breast cancer growth, suggesting additional ligands and/or co-receptors may be needed to fully activate signaling. These data collectively support the notion that FGFR4 is an important mediator of endocrine resistance in ILC, warranting further characterization of phenotypic effects and mechanistic studies of signaling alterations.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Levine, Kevinlevine.kevin@pitt.edukml1160000-0001-6859-3461
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorOesterreich, Steffioesterreichs@upmc.edusto16
Committee ChairDeFrances, Marie C.defrancesmc@upmc.edumcd14
Committee MemberJankowitz, Rachel C.jankowitzr@upmc.edurcj8
Committee MemberLocker, JosephJLOCKER@pitt.edu
Committee MemberTsang, Michaeltsang@pitt.edu
Committee MemberTseng, George C.ctseng@pitt.edu
Date: 8 January 2019
Date Type: Publication
Defense Date: 3 December 2018
Approval Date: 8 January 2019
Submission Date: 22 December 2018
Access Restriction: 3 year -- Restrict access to University of Pittsburgh for a period of 3 years.
Number of Pages: 117
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Cellular and Molecular Pathology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Breast cancer, metastasis, genomics, lobular cancer
Date Deposited: 08 Jan 2019 19:56
Last Modified: 08 Jan 2019 19:56
URI: http://d-scholarship.pitt.edu/id/eprint/35858

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