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Breast cancer subtype dictates DNA methylation and ALDH1A3-mediated expression of tumor suppressor RARRES1
Dalhousie Univ, Dept Pathol, Halifax, NS, Canada..
Dalhousie Univ, Dept Microbiol & Immunol, Halifax, NS, Canada..
Dalhousie Univ, Dept Pathol, Halifax, NS, Canada..
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Biology Education Centre. Dalhousie Univ, Dept Pathol, Halifax, NS, Canada.
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2016 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 28, 44096-44112 p.Article in journal (Refereed) Published
Abstract [en]

Breast cancer subtyping, based on the expression of hormone receptors and other genes, can determine patient prognosis and potential options for targeted therapy. Among breast cancer subtypes, tumors of basal-like and claudin-low subtypes are typically associated with worse patient outcomes, are primarily classified as triple-negative breast cancers (TNBC), and cannot be treated with existing hormone-receptor-targeted therapies. Understanding the molecular basis of these subtypes will lead to the development of more effective treatment options for TNBC. In this study, we focus on retinoic acid receptor responder 1 (RARRES1) as a paradigm to determine if breast cancer subtype dictates protein function and gene expression regulation. Patient tumor dataset analysis and gene expression studies of a 26 cell-line panel, representing the five breast cancer subtypes, demonstrate that RARRES1 expression is greatest in basal-like TNBCs. Cell proliferation and tumor growth assays reveal that RARRES1 is a tumor suppressor in TNBC. Furthermore, gene expression studies, Illumina HumanMethylation450 arrays, and chromatin immunoprecipitation demonstrate that expression of RARRES1 is retained in basal-like breast cancers due to hypomethylation of the promoter. Additionally, expression of the cancer stem cell marker, aldehyde dehydrogenase 1A3, which provides the required ligand (retinoic acid) for RARRES1 transcription, is also specific to the basal-like subtype. We functionally demonstrate that the combination of promoter methylation and retinoic acid signaling dictates expression of tumor suppressor RARRES1 in a subtype-specific manner. These findings provide a precedent for a therapeutically-inducible tumor suppressor and suggest novel avenues of therapeutic intervention for patients with basal-like breast cancer.

Place, publisher, year, edition, pages
2016. Vol. 7, no 28, 44096-44112 p.
Keyword [en]
breast cancer, RARRES1, retinoic acid, ALDH1A3, DNA methylation
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-308046DOI: 10.18632/oncotarget.9858ISI: 000385395700092OAI: oai:DiVA.org:uu-308046DiVA: diva2:1049190
Available from: 2016-11-23 Created: 2016-11-23 Last updated: 2016-11-23Bibliographically approved

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