title: Characterization of CD44+ALDH1+Ki-67- Cells in Non-malignant and Neoplastic Lesions of the Breast.
abstract: Cancer stem cells are tumor cells that present self-renewal, clonal tumor initiation capacity and clonal long-term repopulation potential. We have previously demonstrated that the co-expression of the breast cancer stem cell (BCSC) markers hyaluronan receptor (CD44) and aldehyde dehydrogenase-1 (ALDH1) in ductal carcinomas in situ could be determinant for disease progression. Combining these established BCSC markers with Ki-67 to evaluate quiescence we sought to identify, evaluate the distribution and estimate the mean percentages of CD44(+)ALDH1(+)Ki-67(-) breast cells.
  
  
  
  Triple-immunohistochemistry for CD44, ALDH1 and Ki-67 was applied in a series of 16 normal, 54 non-malignant and 155 malignant breast tissues. Clinical relevance was inferred by associations with markers of breast cancer behavior, progression and survival.
  
  
  
  The mean percentages of cells with this phenotype increased significantly from non-malignant lesions to high-grade ductal carcinomas in situ, decreasing in invasive ductal carcinomas, as also evidenced by an inverse correlation with histological grade and tumor size. The mean percentage of CD44(+)ALDH1(+)Ki-67(-) cells was also significantly higher in women who developed distant metastasis and died due to breast cancer, and a significant association with human epidermal growth factor type 2 (HER2) negativity was observed.
  
  
  
  Our novel findings indicate that CD44(+)ALDH1(+)Ki-67(-) tumor cells may favor distant metastasis and can predict overall survival in patients with ductal carcinomas of the breast. More importantly, quiescence may have a crucial role for tumor progression, treatment resistance and metastatic ability of BCSCs.
authors.affiliation: Pathology and Molecular Immunology Department, Abel Salazar Institute of Biomedical Sciences, University of Porto, Porto, Portugal Department of Pathology, Portuguese Oncology Institute, Porto, Portugal arnaudcpaula@hotmail.com calopes@icbas.up.pt.
authors.forename: Arnaud
authors.initials: A
authors.lastname: DA Cruz Paula
authors.affiliation: Pathology and Molecular Immunology Department, Abel Salazar Institute of Biomedical Sciences, University of Porto, Porto, Portugal Unit for Multidisciplinary Biomedical Research, Abel Salazar Institute of Biomedical Sciences, University of Porto, Porto, Portugal Basic and Clinical Research on Iron Biology, Institute of Molecular and Cell Biology/i3S, Porto, Portugal.
authors.forename: Oriana
authors.initials: O
authors.lastname: Marques
authors.affiliation: Department of Pathology, Porto Hospital Centre, Porto, Portugal.
authors.forename: Rita
authors.initials: R
authors.lastname: Sampaio
authors.affiliation: Pathology and Molecular Immunology Department, Abel Salazar Institute of Biomedical Sciences, University of Porto, Porto, Portugal Basic and Clinical Research on Iron Biology, Institute of Molecular and Cell Biology/i3S, Porto, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Rosa
authors.affiliation: Department of Pathology, Porto Hospital Centre, Porto, Portugal.
authors.forename: José
authors.initials: J
authors.lastname: Garcia
authors.affiliation: Pathology and Molecular Immunology Department, Abel Salazar Institute of Biomedical Sciences, University of Porto, Porto, Portugal.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Rêma
authors.affiliation: Pathology and Molecular Immunology Department, Abel Salazar Institute of Biomedical Sciences, University of Porto, Porto, Portugal.
authors.forename: Maria
authors.initials: M
authors.lastname: DE Fátima Faria
authors.affiliation: Faculty of Medicine, University of Porto, Porto, Portugal Science Diffusion, Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal.
authors.forename: Paula
authors.initials: P
authors.lastname: Silva
authors.affiliation: Department of Pathology, Porto Hospital Centre, Porto, Portugal.
authors.forename: Ramón
authors.initials: R
authors.lastname: Vizcaíno
authors.affiliation: Pathology and Molecular Immunology Department, Abel Salazar Institute of Biomedical Sciences, University of Porto, Porto, Portugal Department of Pathology, Portuguese Oncology Institute, Porto, Portugal arnaudcpaula@hotmail.com calopes@icbas.up.pt.
authors.forename: Carlos
authors.initials: C
authors.lastname: Lopes
mesh_terms: D000328:Adult; D000080924:Aldehyde Dehydrogenase 1 Family; D001940:Breast / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism* / Q000401:mortality; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism* / Q000401:mortality; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000378:metabolism*; D019394:Ki-67 Antigen / Q000378:metabolism*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010641:Phenotype; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D050697:Retinal Dehydrogenase / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D000080924:Aldehyde Dehydrogenase 1 Family; D018960:Hyaluronan Receptors; D007527:Isoenzymes; D019394:Ki-67 Antigen; D018719:Erb-b2 Receptor Tyrosine Kinases; D050697:Retinal Dehydrogenase; C497483:CD44 protein, human; C510223:ALDH1A1 protein, human; C508053:ERBB2 protein, human
keywords: ALDH1; Breast cancer; CD44; breast cancer stem cell markers; cancer stem cell model; quiescence