title: P-cadherin is coexpressed with CD44 and CD49f and mediates stem cell properties in basal-like breast cancer.
abstract: Although the luminal progenitor cell of the normal mammary gland hierarchy has been proposed as the cell-of-origin for basal-like breast cancers, finding the cancer stem cell (CSC) phenotype for this malignancy has proven a difficult task, mostly due to the lack of specific markers. Recently, basal-like sporadic and familial cases of breast cancer have been linked to BRCA1 gene inactivation, which enables the upregulation of the target-repressed CDH3/P-cadherin gene, an important biomarker of basal-like breast carcinomas. Previously, we demonstrated that P-cadherin overexpression can mediate aggressive behavior in these tumors. Thus, our aim was to test whether P-cadherin mediates stem cell properties in basal-like breast carcinomas. Using a series of breast cancer cell lines and primary tumors, we showed that P-cadherin was directly associated with the expression of the breast stem markers CD44, CD49f, and aldehyde dehydrogenase 1 in the basal subtype. Moreover, cell population enriched for P-cadherin expression comprised increased in vitro mammosphere-forming efficiency and capacity to grow colonies in three-dimensional cultures as well as greater tumorigenicity. Importantly, an association was found with stem-/progenitor-like phenotypes of the breast, including the luminal progenitor population, CD49f(+) CD24(+). Additionally, P-cadherin expression conferred resistance to x-ray-induced cell death, sustaining a role for this molecule in another stem cell property. In summary, we demonstrated, for the first time, that P-cadherin mediates stem cell properties, which could be explored in order to better define the CSC phenotype of basal-like breast tumors and the cell-of-origin of this malignancy.
authors.affiliation: IPATIMUP-Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal.
authors.forename: André Filipe
authors.initials: AF
authors.lastname: Vieira
authors.forename: Sara
authors.initials: S
authors.lastname: Ricardo
authors.forename: Matthew Paul
authors.initials: MP
authors.lastname: Ablett
authors.forename: Maria Rita
authors.initials: MR
authors.lastname: Dionísio
authors.forename: Nuno
authors.initials: N
authors.lastname: Mendes
authors.forename: André
authors.initials: A
authors.lastname: Albergaria
authors.forename: Gillian
authors.initials: G
authors.lastname: Farnie
authors.forename: Renê
authors.initials: R
authors.lastname: Gerhard
authors.forename: Jorge F
authors.initials: JF
authors.lastname: Cameselle-Teijeiro
authors.forename: Raquel
authors.initials: R
authors.lastname: Seruca
authors.forename: Fernando
authors.initials: F
authors.lastname: Schmitt
authors.forename: Robert B
authors.initials: RB
authors.lastname: Clarke
authors.forename: Joana
authors.initials: J
authors.lastname: Paredes
mesh_terms: D000080924:Aldehyde Dehydrogenase 1 Family; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D015820:Cadherins / Q000096:biosynthesis*; D016923:Cell Death / Q000528:radiation effects; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis*; D039503:Integrin alpha6 / Q000096:biosynthesis*; D007527:Isoenzymes / Q000096:biosynthesis; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D018295:Neoplasms, Basal Cell / Q000378:metabolism* / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D050697:Retinal Dehydrogenase / Q000096:biosynthesis; D014965:X-Rays
chemical_list: C497483:CD44 protein, human; D015820:Cadherins; D018960:Hyaluronan Receptors; D039503:Integrin alpha6; D007527:Isoenzymes; D009363:Neoplasm Proteins; D000080924:Aldehyde Dehydrogenase 1 Family; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase