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Functional investigation of ESR1 fusions identified in endocrine therapy refractory estrogen receptor positive breast cancer

Erdogan-Yildirim, Zeynep (2019) Functional investigation of ESR1 fusions identified in endocrine therapy refractory estrogen receptor positive breast cancer. Master's Thesis, University of Pittsburgh. (Unpublished)

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Metastatic estrogen receptor (ER)-positive breast cancer is an incurable disease that remains a clinical challenge and a public health burden. Over 40,000 women die each year from breast cancer and over 90% of these are due to metastatic disease. Although there has been great success with anti-endocrine treatment, most patients with metastatic disease develop resistance during the course of therapy. Loss of ER or missense mutations in the ligand-binding domain (LBD) of ER are reported as causal mechanisms of resistance. Recently, our laboratory showed that ESR1 fusions involving loss of LBD, play a role in lack of response to therapy. Only limited knowledge exists on the actual frequency and functional role of ESR1 fusions. Hence, I aimed to expand the search for further ESR1 fusions in advanced breast cancer disease and to characterize the functional role of ESR1 fusions (ESR1-DAB2, ESR1-GYG1 and ESR1-SOX9) our lab published earlier along with the ESR1-LPP fusion found in a PDX-model.
Screening of RNA-seq data of primary-metastatic paired breast tumors (n=45) in University of Pittsburgh cohort and metastatic BrCa (n=91) in the MET500 cohort revealed a total of five ESR1 fusions sharing identical breakpoint with ESR1-YAP1 fusion. ESR1-GYG1 was the only ESR1 fusion identified in the Pitt-cohort. For functional assessment, the ESR1 fusions were transiently and stably transfected into cell lines. The immunofluorescence staining confirmed the predominant nuclear localization of the ESR1 fusions, while ESR1-LPP and ESR1-GYG1 fusions additionally displayed cytoplasmic localization. ER activity assays via luciferase assay and qRT-PCR demonstrated estrogen-independent constitutive activity of ESR1 fusions that is unresponsive to anti-endocrine treatment. While ESR1-DAB2 and ESR1-SOX9 fusions induced the transcription of estrogen-responsive genes, only ESR1-SOX9 demonstrated statistically significant estrogen-independent proliferation in stable expressing T47D cells. Overall, active ESR1 fusions may have a critical role in developing anti-endocrine resistance and promoting tumor progression. Since ESR1 fusions with loss of LBD are recurrent in therapy-refractory ER-positive breast cancer, further comprehensive studies are needed (1) to determine their true frequency, (2) to understand their mechanism of action and (3) to determine their value as prognostic and therapeutic biomarkers.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Erdogan-Yildirim, Zeynepzee5@pitt.eduzee5
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorLee, Adrianleeav@upmc.eduavl10
Committee MemberMinster, Ryanrminster@pitt.edurminster
Committee MemberUrban, Zsolturbanz@pitt.eduurbanz
Date: 21 June 2019
Date Type: Publication
Defense Date: 13 February 2019
Approval Date: 21 June 2019
Submission Date: 28 March 2019
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 101
Institution: University of Pittsburgh
Schools and Programs: School of Public Health > Human Genetics
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: Breast Cancer, endocrine treatment resistant, metastatic, estrogen receptor, ESR1, fusion, ESR1 fusions
Date Deposited: 21 Jun 2019 18:07
Last Modified: 21 Jun 2019 18:07


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