P-Cadherin Is Coexpressed with CD44 and CD49f and Mediates Stem Cell Properties in Basal-like Breast Cancer

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‐...

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Published in:	Stem cells (Dayton, Ohio) Vol. 30; no. 5; pp. 854 - 864
Main Authors:	Vieira, André Filipe, Ricardo, Sara, Ablett, Matthew Paul, Dionísio, Maria Rita, Mendes, Nuno, Albergaria, André, Farnie, Gillian, Gerhard, Renê, Cameselle-Teijeiro, Jorge F., Seruca, Raquel, Schmitt, Fernando, Clarke, Robert B., Paredes, Joana
Format:	Journal Article
Language:	English
Published:	Hoboken Wiley Subscription Services, Inc., A Wiley Company 01-05-2012 Oxford University Press
Subjects:	Aldehyde Dehydrogenase 1 Family Basal-like breast cancer Biomarker Breast cancer Breast Neoplasms - metabolism Breast Neoplasms - pathology Cadherins - biosynthesis Cancer stem cells CDH3 gene Cell Death - radiation effects Cell Line, Tumor Female Gene Expression Regulation, Neoplastic Humans Hyaluronan Receptors - biosynthesis Integrin alpha6 - biosynthesis Isoenzymes - biosynthesis Neoplasm Proteins - biosynthesis Neoplasms, Basal Cell - metabolism Neoplasms, Basal Cell - pathology Neoplastic Stem Cells - metabolism Neoplastic Stem Cells - pathology P-cadherin Retinal Dehydrogenase - biosynthesis Stem cells Tumors X-Rays
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Summary:	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. STEM CELLS 2012;30:854–864
Bibliography:	POPH-QREN-Tipology 4.2 Fundação Gulbenkian, Portugal - No. Project 96633-2010 Fundação Gulbenkian ArticleID:STEM1075 ark:/67375/WNG-BH2G361T-S Disclosure of potential conflicts of interest is found at the end of this article. First published online in STEM CELLSEXPRESS March 2, 2012. FCT SFRH/BD/41363/2007 Author contributions: A.F.V.: conception and design, collection and/or assembly of data, data analysis and interpretation, and manuscript writing; S.R.: collection and/or assembly of data and data analysis and interpretation; M.P.A., M.R.D., and N.M.: collection and/or assembly of data; A.A., G.F., R.G., R.S., and F.S.: data analysis and interpretation; J.F.C.-T.: provision of study material or patients; R.B.C.: conception and design, provision of study material or patients, and data analysis and interpretation; J.P.: conception and design, data analysis and interpretation, manuscript writing, and final approval of manuscript. Fundação Champalimaud, Portuguese Ministry of Science, Technology and Higher Education and FCT, Portugal Programa Ciência 2007 istex:0A6D7CB4223BDCFAA086557F16C290713788653A First published online in S C XPRESS E March 2, 2012. Author contributions: A.F.V.: conception and design, collection and/or assembly of data, data analysis and interpretation, and manuscript writing; S.R.: collection and/or assembly of data and data analysis and interpretation; M.P.A., M.R.D., and N.M.: collection and/or assembly of data; A.A., G.F., R.G., R.S., and F.S.: data analysis and interpretation; J.F.C.‐T.: provision of study material or patients; R.B.C.: conception and design, provision of study material or patients, and data analysis and interpretation; J.P.: conception and design, data analysis and interpretation, manuscript writing, and final approval of manuscript. TEM ELLS Telephone: +351‐22‐5570700; Fax: +351‐22‐5570799 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1066-5099 1549-4918
DOI:	10.1002/stem.1075