Yates, Megan
(2022)
Functional Characterization and Clinical Prevalence of ESR1 Fusions in Advanced Endocrine Resistant Breast Cancer.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
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.
Share
| Citation/Export: |
|
| Social Networking: |
|
Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
|
| 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 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/43750 |
Metrics
Monthly Views for the past 3 years
Plum Analytics
Actions (login required)
 |
View Item |
![[img]](http://d-scholarship.pitt.edu/style/images/fileicons/application_pdf.png)
![[feed]](/images/feed-icon-32x32.png){kind=icon}