Elucidating the role of the gap 0 switch 2 gene in breast cancer

Corbet, Andrea K

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https://hdl.handle.net/2142/121479 Copy

Description

Title

Elucidating the role of the gap 0 switch 2 gene in breast cancer

Author(s)

Corbet, Andrea K

Issue Date

2023-07-14

Director of Research (if dissertation) or Advisor (if thesis)

Spinella, Michael

Doctoral Committee Chair(s)

Spinella, Michael

Committee Member(s)

• Bagchi, Indrani
• Nelson, Erik
• Bonthuis, Paul

Department of Study

Comparative Biosciences

Discipline

VMS - Comparative Biosciences

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

• Breast cancer
• Antiestrogen
• Epithelial mesenchymal transition
• Estrogen receptor
• G0S2

Abstract

Breast cancer has the second highest cancer mortality rate in women in the United States. While current treatments have significantly improved patient outlook, breast cancer patients continue to face the risk of developing treatment resistance and experiencing relapse. Additionally, triple-negative breast cancer remains a lethal disease with few efficient therapeutic targets compared to receptor-positive breast cancer. This thesis summarizes the investigation of the gap 0 switch 2 gene and its impact on estrogen-receptor positive breast cancer and triple-negative breast cancer. G0/G1 switch gene 2 (G0S2) is known to inhibit lipolysis by inhibiting adipose triglyceride lipase (ATGL). In this report, we dissect the role of G0S2 in ER+ versus ERbreast cancer. Overexpression of G0S2 in ER- cells increased cell proliferation, while G0S2 overexpression in ER+ cells decreased cell proliferation. Transcriptome analysis revealed that G0S2 mediated distinct but overlapping transcriptional responses in ERand ER+ cells. G0S2 reduced expression of genes associated with an epithelial phenotype, especially in ER- cells, including CDH1, ELF3, STEAP4 and TACSTD2, suggesting promotion of the epithelial-mesenchymal transition (EMT). G0S2 also repressed the expression of genes involved in estrogen signaling and estrogen receptor target gene signatures, especially in ER+ cells, including TFF1 and TFF3. In addition, G0S2 overexpression increased cell migration in ER- cells and increased estrogen deprivation sensitivity in ER+ cells. Interestingly, two genes downstream of ATGL in fat utilization and very important in steroid hormone biosynthesis, HMGCS1 and HMGCS2, were downregulated in G0S2 overexpressing ER+ cells. In addition, HSD17B11, a gene that converts estradiol to its less estrogenic derivative, estrone, was highly upregulated in iii G0S2 overexpressing ER+ cells, suggesting G0S2 overexpression has a negative effect on estradiol production and maintenance. High expression of G0S2 and HSD17B11 was associated with improved relapse-free survival in breast cancer patients while high expression of HMGSC1 was associated with poor survival. Finally, we deleted G0S2 in breast cancer-prone MMTV-PyMT mice. Our data indicates a complex role for G0S2 in breast cancer, dependent on ER status, that may be partially mediated by suppression of the estrogen signaling pathway.

Graduation Semester

2023-08

Type of Resource

Thesis

Handle URL

https://hdl.handle.net/2142/121479

Copyright and License Information

Copyright 2023 Andrea Corbet

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