Regulation of the Glucocorticoid Receptor Promoter and Its Prognostic Value in Tamoxifen-Treated ER+ Breast Cancer
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Authors
Snider, Hilary
Date
Type
thesis
Language
eng
Keyword
Breast Cancer , Glucocorticoid Receptor , Biomarker , Tamoxifen , Estrogen Receptor , Methylation , NR3C1
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Abstract
Most breast cancers are estrogen receptor positive (ER+) and therefore benefit from endocrine-based therapies such as tamoxifen which impair estrogen signaling. However, resistance is a major clinical concern and ER status alone is insufficient to predict treatment response. As a result, additional biomarkers are needed to predict resistance. The glucocorticoid receptor (GR) is an attractive candidate because it functions as a tumor suppressor in ER+ breast cancer and low GR expression has been associated with poor outcome in tamoxifen-treated patients. GR promoter methylation occurs frequently in ER+ tumors and coincides with particularly low GR expression. To investigate GR methylation as a potential biomarker, we developed a targeted multiplex bisulfite sequencing assay to detect promoter methylation in archival tumor samples. With this assay, we evaluated the prognostic and predictive value of GR methylation in ER+ patients from the CCTG MA.12 tamoxifen clinical trial. Region-specific GR promoter methylation was an independent marker of poor prognosis and identified a subset of patients with especially poor survival, particularly in the absence of tamoxifen treatment. This provides a foundation for the continued development of GR methylation as a prognostic marker in ER+ breast cancer.
Given the tumor suppressive role of GR in ER+ breast cancer, we examined the regulation of GR expression in the context of tamoxifen treatment. GR mRNA levels increased with tamoxifen in ER+ but not ER− breast cancer cells, suggesting ER is involved in regulating GR expression. The GR promoter is particularly complex with multiple first exons. By adapting 5’RACE for next-generation sequencing, we established that increased GR expression was mediated through the same exons in the proximal promoter in tamoxifen-treated ER+ cells. We then carried out a functional analysis of this promoter region in ER− cells transiently expressing ER or naturally-occurring ER mutants (Y537S or D538G). Our findings suggest tamoxifen upregulates GR through an ER-dependent non-classical signaling mechanism with differing characteristics depending on the ER mutation. Since GR has an established antiproliferative effect on ER+ breast cancer cells, tamoxifen-induced GR upregulation could be an important factor influencing treatment response. This work may have important clinical implications for tamoxifen-treated patients, including those with acquired ER mutations.
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ProQuest PhD and Master's Theses International Dissemination Agreement
Intellectual Property Guidelines at Queen's University
Copying and Preserving Your Thesis
This publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.