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

Functional Characterization and Clinical Prevalence of ESR1 Fusions in Advanced Endocrine Resistant Breast Cancer

Yates, Megan (2022) Functional Characterization and Clinical Prevalence of ESR1 Fusions in Advanced Endocrine Resistant Breast Cancer. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

[img] PDF
Accepted Version
Restricted to University of Pittsburgh users only until 29 September 2024.

Download (7MB) | Request a Copy


Breast cancer is a leading cause of female mortality and despite advancements in diagnostics and personalized therapeutics, metastatic disease largely remains incurable due to drug resistance. The druggable estrogen receptor (ER, ESR1), overexpressed in two-thirds of all breast cancer, evolves in 30% of tumors exposed to endocrine therapy consequently resulting in treatment resistance. A more recently discovered mechanism of ER mediated endocrine resistance is ER fusion proteins. ER fusions harbor ESR1 exons 1-6 fused to an in-frame gene partner due to an ESR1 intron 6 translocation break. Our lab has demonstrated that ER fusion proteins, which lack the C-terminal ligand-binding domain (LBD), recapitulate phenotypes of ER proteins harboring endocrine-resistant point mutations occurring in the LBD. Our research goals aim to 1) understand fusion mechanisms of resistance and 2) determine fusion prevalence and emergence.
To investigate ER fusion proteins mechanistically, we have stably overexpressed the ER chimera constructs in transgenic breast cancer cell lines engineered to deplete endogenous wildtype ER (ESR1-WT). In this cellular context, we found that ER fusions demonstrate ER hyperactivation through estrogen response element assays and are enriched in oncogenic phenotypes such as enhanced growth, cell survival and migration. Importantly, fusion activity is robust in the absence of the ER ligand, estradiol, as well as in the presence of endocrine therapies, implying ER fusion proteins function in a ligand independent, endocrine resistant manner. ER fusion hyperactivity was observed in both invasive ductal and lobular carcinoma cell lines, albeit at varying magnitudes depending on the 3’ fusion partner and phenotype being assessed indicating a cellular context dependent phenotype. Enrichment in MYC signaling networks was shared among all fusion protein transcriptomes. In addition, novel ESR1 exons 1-6 fusions have been discovered in endogenous patient derived xenograft models and organoids. We have further developed a novel ER fusion detection method, EnRich. The EnRich probe set targets intronic and exonic ESR1, the upstream promoter region and select oncogenic genes. Comprehensive detection and functional evaluation of ER fusion proteins will provide clinicians and patients with better understanding of tumor endocrine-resistant prevalence and discovery of more effective treatment options.


Social Networking:
Share |


Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Yates, Meganmey29@pitt.edumey290000-0002-5932-1592
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairZervantonakis, Ioannis K.ioz1@pitt.eduioz1
Thesis AdvisorOesterreich, Steffisto16@pitt.edusto16
Committee MemberLee, Adrian V.leeav@upmc.eduavl10
Committee MemberDeFrances, Marie C.defrancesmc@upmc.edumcd14
Committee MemberXiaosong, Wangxiaosongw@pitt.eduxiaosongw
Committee MemberLucas, Peter C.lucaspc@upmc.edupcl8
Date: 30 September 2022
Defense Date: 13 October 2022
Approval Date: 29 September 2023
Submission Date: 21 October 2022
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 262
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Integrative Systems Biology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Estrogen Receptor; Breast Cancer; Endocrine Resistance; Fusions
Date Deposited: 29 Sep 2023 18:53
Last Modified: 29 Sep 2023 18:53


Monthly Views for the past 3 years

Plum Analytics

Actions (login required)

View Item View Item