title: Aldehyde dehydrogenase activity of breast cancer stem cells is primarily due to isoform ALDH1A3 and its expression is predictive of metastasis.
abstract: Cancer stem cells (CSCs) are proposed to initiate cancer and propagate metastasis. Breast CSCs identified by aldehyde dehydrogenase (ALDH) activity are highly tumorigenic in xenograft models. However, in patient breast tumor immunohistological studies, where CSCs are identified by expression of ALDH isoform ALDH1A1, CSC prevalence is not correlative with metastasis, raising some doubt as to the role of CSCs in cancer. We characterized the expression of all 19 ALDH isoforms in patient breast tumor CSCs and breast cancer cell lines by total genome microarray expression analysis, immunofluorescence protein expression studies, and quantitative polymerase chain reaction. These studies revealed that ALDH activity of patient breast tumor CSCs and cell lines correlates best with expression of another isoform, ALDH1A3, not ALDH1A1. We performed shRNA knockdown experiments of the various ALDH isoforms and found that only ALDH1A3 knockdown uniformly reduced ALDH activity of breast cancer cells. Immunohistological studies with fixed patient breast tumor samples revealed that ALDH1A3 expression in patient breast tumors correlates significantly with tumor grade, metastasis, and cancer stage. Our results, therefore, identify ALDH1A3 as a novel CSC marker with potential clinical prognostic applicability, and demonstrate a clear correlation between CSC prevalence and the development of metastatic breast cancer.
authors.affiliation: Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Paola
authors.initials: P
authors.lastname: Marcato
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Dean
authors.forename: Da
authors.initials: D
authors.lastname: Pan
authors.forename: Rakhna
authors.initials: R
authors.lastname: Araslanova
authors.forename: Megan
authors.initials: M
authors.lastname: Gillis
authors.forename: Madalsa
authors.initials: M
authors.lastname: Joshi
authors.forename: Lucy
authors.initials: L
authors.lastname: Helyer
authors.forename: Luzhe
authors.initials: L
authors.lastname: Pan
authors.forename: Andrew
authors.initials: A
authors.lastname: Leidal
authors.forename: Shashi
authors.initials: S
authors.lastname: Gujar
authors.forename: Carman A
authors.initials: CA
authors.lastname: Giacomantonio
authors.forename: Patrick W K
authors.initials: PW
authors.lastname: Lee
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008856:Microscopy, Fluorescence; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000201:enzymology* / Q000473:pathology*; D050697:Retinal Dehydrogenase; D023041:Xenograft Model Antitumor Assays
chemical_list: D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase