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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.

Original publication

DOI

10.1002/stem.1075

Type

Journal article

Journal

Stem cells (Dayton, Ohio)

Publication Date

05/2012

Volume

30

Pages

854 - 864

Addresses

IPATIMUP-Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal.

Keywords

Cell Line, Tumor, Humans, Neoplasms, Basal Cell, Breast Neoplasms, Isoenzymes, Cadherins, Antigens, CD44, Integrin alpha6, Neoplasm Proteins, Cell Death, Gene Expression Regulation, Neoplastic, X-Rays, Female, Retinal Dehydrogenase, Neoplastic Stem Cells