{"id":{"repo_id":"queens","oai_identifier":"oai:queensu.scholaris.ca:1974/27705"},"canonical_url":"https://search.dev.ndltd.org/etd/queens/oai:queensu.scholaris.ca:1974/27705","repository":{"repo_id":"queens","name":"Queens University","base_url":"https://qspace.library.queensu.ca/server/oai/request"},"display":{"title":"Regulation of the Glucocorticoid Receptor Promoter and Its Prognostic Value in Tamoxifen-Treated ER+ Breast Cancer","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.","abstract_html":"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.","abstract_has_math":false,"creators":["Snider, Hilary"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":"Pathology and Molecular Medicine","school":null,"contributors":[],"advisors":["Mueller, Christopher"],"committee_chairs":[],"committee_members":[],"year":null,"date_issued":"","date_published":null,"updated_at":"2026-07-27T20:35:19Z","subjects":["Breast Cancer","Glucocorticoid Receptor","Biomarker","Tamoxifen","Estrogen Receptor","Methylation","NR3C1"],"languages":["eng"],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/1974/27705","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.department","label":"Department","values":["Pathology and Molecular Medicine"]},{"key":"dc:contributor.supervisor","label":"Supervisor","values":["Mueller, Christopher"]},{"key":"dc:creator","label":"Author","values":["Snider, Hilary"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2020-04-15T18:39:00Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2020-04-15T18:39:00Z"]},{"key":"dc:type","label":"Dc Type","values":["thesis"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Breast Cancer","Glucocorticoid Receptor","Biomarker","Tamoxifen","Estrogen Receptor","Methylation","NR3C1"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language.iso","label":"Language (ISO)","values":["eng"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["http://hdl.handle.net/1974/27705"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["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."]},{"key":"dc:description.degree","label":"Dc Description Degree","values":["PhD"]},{"key":"dc:title","label":"Title","values":["Regulation of the Glucocorticoid Receptor Promoter and Its Prognostic Value in Tamoxifen-Treated ER+ Breast Cancer"]}]}],"canonical_facts":{"dc:contributor.department":["Pathology and Molecular Medicine"],"dc:contributor.supervisor":["Mueller, Christopher"],"dc:creator":["Snider, Hilary"],"dc:date.accessioned":["2020-04-15T18:39:00Z"],"dc:date.available":["2020-04-15T18:39:00Z"],"dc:description.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."],"dc:description.degree":["PhD"],"dc:identifier.uri":["http://hdl.handle.net/1974/27705"],"dc:language.iso":["eng"],"dc:subject":["Breast Cancer","Glucocorticoid Receptor","Biomarker","Tamoxifen","Estrogen Receptor","Methylation","NR3C1"],"dc:title":["Regulation of the Glucocorticoid Receptor Promoter and Its Prognostic Value in Tamoxifen-Treated ER+ Breast Cancer"],"dc:type":["thesis"]},"updated_at":"2026-07-27T20:35:19Z"}