Breast cancer subtype dictates DNA methylation and ALDH1A3-mediated expression of tumor suppressor RARRES1.
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.
Department of Pathology, Dalhousie University, Halifax, NS, Canada.
Krysta M
KM
Coyle
Department of Microbiology & Immunology, Dalhousie University, Halifax, NS, Canada.
J Patrick
JP
Murphy
Department of Pathology, Dalhousie University, Halifax, NS, Canada.
Dejan
D
Vidovic
Department of Pathology, Dalhousie University, Halifax, NS, Canada.|Department of Biology Education Center, Uppsala University, Uppsala, Sweden.
Ahmad
A
Vaghar-Kashani
Department of Pathology, Dalhousie University, Halifax, NS, Canada.|Department of Microbiology & Immunology, Dalhousie University, Halifax, NS, Canada.
Cheryl A
CA
Dean
Department of Pathology, Dalhousie University, Halifax, NS, Canada.
Mohammad
M
Sultan
Department of Pathology, Dalhousie University, Halifax, NS, Canada.
Derek
D
Clements
Department of Microbiology & Immunology, Dalhousie University, Halifax, NS, Canada.
Melissa
M
Wallace
Department of Pathology, Dalhousie University, Halifax, NS, Canada.
Margaret L
ML
Thomas
Department of Psychology and Neuroscience, and Psychiatry, Dalhousie University, Halifax, NS, Canada.
Amos
A
Hundert
Department of Pathology, Dalhousie University, Halifax, NS, Canada.|Department of Surgery, Dalhousie University, Halifax, NS, Canada.
Carman A
CA
Giacomantonio
Department of Surgery, Dalhousie University, Halifax, NS, Canada.
Lucy
L
Helyer
Department of Pathology, Dalhousie University, Halifax, NS, Canada.|Department of Microbiology & Immunology, Dalhousie University, Halifax, NS, Canada.|Department of Quality and System Performance, IWK Health Centre, Halifax, NS, Canada.
Shashi A
SA
Gujar
Department of Pathology, Dalhousie University, Halifax, NS, Canada.|Department of Microbiology & Immunology, Dalhousie University, Halifax, NS, Canada.
Patrick W K
PW
Lee
Department of Psychology and Neuroscience, and Psychiatry, Dalhousie University, Halifax, NS, Canada.
Ian C G
IC
Weaver
Department of Pathology, Dalhousie University, Halifax, NS, Canada.
Paola
P
Marcato
D000445:Aldehyde Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D019175:DNA Methylation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D011379:Prognosis; D060066:Protein Interaction Maps / Q000235:genetics; D034622:RNA Interference; D014183:Transplantation, Heterologous; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D047368:Tumor Burden / Q000235:genetics
D008565:Membrane Proteins; C452562:RARRES1 protein, human; D000445:Aldehyde Oxidoreductases; C018699:aldehyde dehydrogenase (NAD(P)+)
ALDH1A3; DNA methylation; RARRES1; breast cancer; retinoic acid