title: Stem cell biomarker ALDH1A1 in breast cancer shows an association with prognosis and clinicopathological variables that is highly cut-off dependent.
abstract: OBJECTIVE
  Aldehyde dehydrogenase family 1 member A1 (ALDH1A1) is a putative marker of breast cancer stem cells (CSCs) with prognostic implications when expressed in cancer or stroma. However, previous results are contradictory and we therefore aimed to further evaluate the impact of ALDH1A1 on distant disease-free survival (DDFS) and correlation with clinicopathological variables in breast cancer, specifically by evaluating different cut-offs.
  
  
  METHODS
  Two breast cancer cohorts (N=216 and N=210) were evaluated with immunohistochemistry for ALDH1A1 on tissue microarrays with three different cut-offs in cancer cells and in stromal cells. The association of ALDH1A1 with DDFS and other clinicopathological variables was assessed. As further validation, gene expression levels of ALDH1A1 and association with survival were analysed in one of the cohorts and a separate cohort.
  
  
  RESULTS
  ALDH1A1 expression in cancer cells was associated with either a better or a worse prognosis, depending on cut-off. Considering weakly stained cancer cells as positive, ALDH1A1+ was associated with a better prognosis in both cohorts. Considering only strongly stained cells as positive, ALDH1A1+ was associated with oestrogen receptor and progesterone receptor negativity in both cohorts and worse prognosis in one of the cohorts. Stromal ALDH1A1 staining was associated with improved DDFS in one cohort. Gene expression analysis showed that a high ALDH1A1 expression was associated with a better prognosis.
  
  
  CONCLUSIONS
  ALDH1A1 is associated with DDFS and clinicopathological variables, both in cancer cells and stroma, but is highly cut-off dependent. Only the strongly ALDH1A1-stained cells show a more aggressive phenotype typical for CSCs.
authors.affiliation: Department of Clinical Sciences Lund, Oncology and Pathology, Lund University, Lund, Sweden.
authors.forename: Martin
authors.identifier: http://orcid.org/0000-0002-2629-9966
authors.initials: M
authors.lastname: Sjöström
authors.affiliation: Department of Clinical Sciences Lund, Oncology and Pathology, Lund University, Lund, Sweden.
authors.forename: Linda
authors.initials: L
authors.lastname: Hartman
authors.affiliation: Department of Clinical Sciences Lund, Oncology and Pathology, Lund University, Lund, Sweden.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Honeth
authors.affiliation: Department of Clinical Sciences Lund, Oncology and Pathology, Lund University, Lund, Sweden Division of Pathology, Skåne University Hospital, Lund, Sweden.
authors.forename: Dorthe
authors.initials: D
authors.lastname: Grabau
authors.affiliation: Department of Clinical Sciences Lund, Oncology and Pathology, Lund University, Lund, Sweden Division of Oncology and Radiation Physics, Skåne University Hospital, Lund, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Malmström
authors.affiliation: Department of Clinical Sciences Lund, Oncology and Pathology, Lund University, Lund, Sweden.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Hegardt
authors.affiliation: Department of Clinical Sciences Lund, Oncology and Pathology, Lund University, Lund, Sweden.
authors.forename: Mårten
authors.initials: M
authors.lastname: Fernö
authors.affiliation: Department of Clinical Sciences Lund, Oncology and Pathology, Lund University, Lund, Sweden Division of Surgery, Skåne University Hospital, Lund, Sweden.
authors.forename: Emma
authors.initials: E
authors.lastname: Niméus
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000444:Aldehyde Dehydrogenase / Q000378:metabolism*; D000080924:Aldehyde Dehydrogenase 1 Family; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D015331:Cohort Studies; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D050697:Retinal Dehydrogenase
chemical_list: D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase
keywords: BREAST CANCER; CANCER STEM CELLS; ENZYMES; ONCOLOGY; TUMOUR MARKERS