Breast cancer subtype dictates DNA methylation and ALDH1A3-mediated expression of tumor suppressor RARRES1
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Krysta M. Coyle1, J. Patrick Murphy2, Dejan Vidovic1, Ahmad Vaghar-Kashani1,3, Cheryl A. Dean1,2, Mohammad Sultan1, Derek Clements1, Melissa Wallace2, Margaret L. Thomas1, Amos Hundert4, Carman A. Giacomantonio1,5, Lucy Helyer5, Shashi A. Gujar1,2,6, Patrick W.K. Lee1,2, Ian C.G. Weaver4, Paola Marcato1
1Department of Pathology, Dalhousie University, Halifax, NS, Canada
2Department of Microbiology & Immunology, Dalhousie University, Halifax, NS, Canada
3Department of Biology Education Center, Uppsala University, Uppsala, Sweden
4Department of Psychology and Neuroscience, and Psychiatry, Dalhousie University, Halifax, NS, Canada
5Department of Surgery, Dalhousie University, Halifax, NS, Canada
6Department of Quality and System Performance, IWK Health Centre, Halifax, NS, Canada
Paola Marcato, email: [email protected]
Keywords: breast cancer, RARRES1, retinoic acid, ALDH1A3, DNA methylation
Received: March 30, 2016 Accepted: May 09, 2016 Published: June 06, 2016
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.
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