title: Aldehyde dehydrogenase 1A3 influences breast cancer progression via differential retinoic acid signaling.
abstract: Aldehyde dehydrogenase (ALDH) 1A enzymes produce retinoic acid (RA), a transcription induction molecule. To investigate if ALDH1A1 or ALDH1A3-mediated RA signaling has an active role in breast cancer tumorigenesis, we performed gene expression and tumor xenograft studies. Analysis of breast patient tumors revealed that high levels of ALDH1A3 correlated with expression of RA-inducible genes with retinoic acid response elements (RAREs), poorer patient survival and triple-negative breast cancers. This suggests a potential link between ALDH1A3 expression and RA signaling especially in aggressive and/or triple-negative breast cancers. In MDA-MB-231, MDA-MB-468 and MDA-MB-435 cells, ALDH1A3 and RA increased expression of RA-inducible genes. Interestingly, ALDH1A3 had opposing effects in tumor xenografts, increasing tumor growth and metastasis of MDA-MB-231 and MDA-MB-435 cells, but decreasing tumor growth of MDA-MB-468 cells. Exogenous RA replaced ALDH1A3 in inducing the same opposing tumor growth and metastasis effects, suggesting that ALDH1A3 mediates these effects by promoting RA signaling. Genome expression analysis revealed that ALDH1A3 induced largely divergent gene expression in MDA-MB-231 and MDA-MB-468 cells which likely resulted in the opposing tumor growth effects. Treatment with DNA methylation inhibitor 5-aza-2'deoxycytidine restored uniform RA-inducibility of RARE-containing HOXA1 and MUC4 in MDA-MB-231 and MDA-MB-468 cells, suggesting that differences in epigenetic modifications contribute to differential ALDH1A3/RA-induced gene expression in breast cancer. In summary, ALDH1A3 induces differential RA signaling in breast cancer cells which affects the rate of breast cancer progression.
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, NS, Canada; Department of Microbiology & Immunology, Dalhousie University, Halifax, NS, Canada. Electronic address: paola.marcato@dal.ca.
authors.forename: Paola
authors.initials: P
authors.lastname: Marcato
authors.affiliation: Department of Microbiology & Immunology, Dalhousie University, Halifax, NS, Canada.
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Dean
authors.affiliation: Department of Oncology, University of Alberta, Edmonton, AB, Canada.
authors.forename: Rong-Zong
authors.initials: RZ
authors.lastname: Liu
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, NS, Canada.
authors.forename: Krysta M
authors.initials: KM
authors.lastname: Coyle
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, NS, Canada.
authors.forename: Moamen
authors.initials: M
authors.lastname: Bydoun
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, NS, Canada.
authors.forename: Melissa
authors.initials: M
authors.lastname: Wallace
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, NS, Canada.
authors.forename: Derek
authors.initials: D
authors.lastname: Clements
authors.affiliation: Department of Surgery, Dalhousie University, Halifax, NS, Canada.
authors.forename: Colin
authors.initials: C
authors.lastname: Turner
authors.affiliation: Department of Surgery, Dalhousie University, Halifax, NS, Canada.
authors.forename: Edward G
authors.initials: EG
authors.lastname: Mathenge
authors.affiliation: Department of Microbiology & Immunology, Dalhousie University, Halifax, NS, Canada; Strategy and Organizational Performance, IWK Health Centre, Halifax, NS, Canada.
authors.forename: Shashi A
authors.initials: SA
authors.lastname: Gujar
authors.affiliation: Department of Surgery, Dalhousie University, Halifax, NS, Canada.
authors.forename: Carman A
authors.initials: CA
authors.lastname: Giacomantonio
authors.affiliation: Department of Oncology, University of Alberta, Edmonton, AB, Canada.
authors.forename: John R
authors.initials: JR
authors.lastname: Mackey
authors.affiliation: Department of Oncology, University of Alberta, Edmonton, AB, Canada.
authors.forename: Roseline
authors.initials: R
authors.lastname: Godbout
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, NS, Canada; Department of Microbiology & Immunology, Dalhousie University, Halifax, NS, Canada. Electronic address: patrick.lee@dal.ca.
authors.forename: Patrick W K
authors.initials: PW
authors.lastname: Lee
mesh_terms: D000445:Aldehyde Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D064593:Heterografts; D006801:Humans; D051379:Mice; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D015398:Signal Transduction; D014212:Tretinoin / Q000378:metabolism*
chemical_list: D009363:Neoplasm Proteins; D014212:Tretinoin; D000445:Aldehyde Oxidoreductases; C018699:aldehyde dehydrogenase (NAD(P)+)
keywords: ALDH1A1; ALDH1A3; Breast cancer; Retinoic acid; Triple-negative
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