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Hotspot Mutations on Estrogen Receptor-α Are Multimodal and Contextual Drivers of Breast Cancer Endocrine Resistance and Metastasis

Li, Zheqi (2020) Hotspot Mutations on Estrogen Receptor-α Are Multimodal and Contextual Drivers of Breast Cancer Endocrine Resistance and Metastasis. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Hotspot mutations in the estrogen receptor alpha (ERα) are frequently detected in ER+ metastatic breast cancer. There is increasing evidence that these mutations confer endocrine resistance and metastatic capacities to breast cancer patients. However, their functional role remains largely unknown. In the first part, we report the generation of genome-edited MCF7 and T47D cell lines harboring Y537S and D538G ESR1 mutations. ESR1 mutations confer ligand-independent growth and endocrine resistance. Transcriptomic analysis revealed highly context-dependent gene expression profiles. I also characterized the critical role of enhanced IGF1R signaling in ESR1 mutant cells through IRS1 upregulation and pointing towards a potential for co-targeting IGF1R and ERα in breast tumors with mutant ESR1. In the second part, I addressed a critical question- whether these mutations contribute to metastatic process, or merely endocrine resistance. I show clinical evidence for the presence of ESR1 mutations exclusively in distant but not in local recurrence. Consistent to transcriptomic profiling of ESR1 mutant tumors, ESR1 mutant cell models exhinit a reprogrammed cell adhesome, which functionally confers enhanced cell-cell contacts while decreasing cell-ECM adhesion. Contextual migratory phenotypes revealed druggable vulnerabilities, which could be exploited by combination of Wnt and ER targeting strategies. Analysis of global ER and FOXA1 binding sites with accessible genome data uncovers loss of FOXA1 dependency of D538G mutated ER and novel FOXA1-driven chormatin. Collectively, these data serve as essential evidence for ESR1 mutations-driven metastasis and provide guidance for future pre-clinical therapeutic strategies. In the third part, I identified that basal markers were highly enriched in ESR1 mutant breast cancers. This could be explained by dual mechanisms inducting basal cytokeratins: a CTCF-driven chromatin loop and progesterone receptor-mediated transactivation. Clinically, high basal cytokeratins are associated with enhanced immune response in ESR1 mutant tumors attributing to the S100A8/9 signaling. Together, these observations show that activating ER mutations confer basal molecular feature and imply immune therapeutic vulnerabilities. In summary, we deciphered the multimodal and contextual role of hotspot ESR1 mutations in breast cancer endocrine resistance, metastasis and gain of basal features. Our study provides mechanistic and therapeutic insights to target these activating mutations in advanced breast cancer patients.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Li, Zheqizhl98@pitt.eduzhl980000-0003-1213-640X
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairDefranco, Donalddod1@pitt.edu
Thesis AdvisorOesterreich, Steffioesterreichs@upmc.edu
Committee MemberZhang, LinZhangLx@upmc.edu
Committee MemberLee, Adrianleeav@upmc.edu
Committee MemberLucas, Peterlucaspc@upmc.edu
Date: 10 June 2020
Date Type: Publication
Defense Date: 6 April 2020
Approval Date: 10 June 2020
Submission Date: 30 April 2020
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 319
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Molecular Pharmacology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Breast Cancer; Estrogen Receptor; Mutations; Endocrine Resistance; Metastasis
Date Deposited: 10 Jun 2020 04:55
Last Modified: 10 Jun 2020 04:55
URI: http://d-scholarship.pitt.edu/id/eprint/38852

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