Document Detail


Identification of a subset of breast carcinomas characterized by expression of cytokeratin 15: relationship between CK15+ progenitor/amplified cells and pre-malignant lesions and invasive disease.
MedLine Citation:
PMID:  19383306     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Recently, we presented evidence--based on the analysis of benign hyperproliferative lesions of the breast--for the presence of cells that express the stem cell marker cytokeratin (CK) 15 in combination with CK19, a protein widely expressed by mammary epithelial cells. Here we report the finding of a subset of breast carcinomas characterized by expression of CK15. CK15 expressing tumors constituted 5% (6 out of 120; 4 of ductal type and 2 of lobular type) of the high-risk breast carcinomas examined by gel-based proteomics and immunohistochemistry. Five out of the six CK15+ carcinomas were CK15+/CK19-. The remaining tumor was mainly composed of cells expressing both CK15 and CK19 (CK15+/CK19+), but it also contained invasive areas with cells expressing only one of these makers (CK15+/CK19- and CK15-/CK19+ cells). To address the relationship between putative luminal progenitor/amplified CK15+ cells and malignant disease, and to determine whether cells/lesions lose expression of CK15 as a result of tumour initiation and/or progression, we searched among our sample set for carcinomas in which invasive tumor areas co-existed with non-malignant cells and hyperproliferative and known pre-malignant lesions. Only one such tumour was found (T71), a CK15-/CK19+/p53+ carcinoma that contained p53 negative non-malignant epithelial cells exhibiting a variety of, CK15/CK19 cellular phenotypes (CK15+/CK19+; CK15+/CK19-; CK15-/CK19+; CK15-/CK19-), often associated with simple columnar cells. Single layers of epithelial cells exhibiting all four CK15/CK19 phenotypes were observed contiguous to areas of atypical ductal hyperplasia that contained p53 positive cells that lost CK15 expression (CK15-/CK19+) and had a very similar phenotype to those of the neighboring ductal carcinoma in situ (DCIS) and invasive cells. The undifferentiated CK15+/CK19+ cells, which had the phenotype CK15+/CK19+/CK14+/CK8+ and -/ER-/PgR-/AR-/CD44+ (weak)/CK17-/p63-/vimentin+/Ki67-/Bcl-2+ (weak)/GATA-3-/p53-, most likely correspond to lineage-restricted luminal progenitor cells able to generate the other more differentiated CK15/CK19 cellular phenotypes, thus giving rise to the daunting intratumour heterogeneity displayed by carcinoma T71. Cells with a very similar phenotype to the CK15+/CK19+ progenitor cells were observed in a juvenile fibroadenoma as well as in the large collecting ducts of the breast. The latter, however, expressed in addition CK14 and had a phenotype (CK15+/CK19+/CK14+/CK8+ (weak)/ER-/PgR-/AR-/CD44+ (weak)/CK17-/p63-/vimentin-/Ki67-/Bcl-2+/GATA-3-/p53-) that resembled that of the putative normal adult breast stem cells as inferred from published data. Further molecular characterization of these progenitor cells as well as unraveling of the signaling pathways that regulate their growth and differentiation may prove invaluable for developing novel therapeutic strategies that target cancer at an early stage.
Authors:
Julio E Celis; Irina Gromova; Teresa Cabezón; Pavel Gromov; Tao Shen; Vera Timmermans-Wielenga; Fritz Rank; José M A Moreira
Related Documents :
9365236 - P53 expression overcomes p21waf1/cip1-mediated g1 arrest and induces apoptosis in human...
17578896 - Low-dose bbr3610 toxicity in colon cancer cells is p53-independent and enhanced by inhi...
17909866 - Synthesis and characterization of new copper thiosemicarbazone complexes with an onns q...
15064746 - Genotoxic stress leads to centrosome amplification in breast cancer cell lines that hav...
20162566 - Cleavage of galectin-3 by matrix metalloproteases induces angiogenesis in breast cancer.
15781466 - The bone-specific expression of runx2 oscillates during the cell cycle to support a g1-...
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2007-09-25
Journal Detail:
Title:  Molecular oncology     Volume:  1     ISSN:  1878-0261     ISO Abbreviation:  Mol Oncol     Publication Date:  2007 Dec 
Date Detail:
Created Date:  2009-04-22     Completed Date:  2009-06-23     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101308230     Medline TA:  Mol Oncol     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  321-49     Citation Subset:  IM    
Affiliation:
Danish Centre for Translational Breast Cancer Research, Copenhagen, Denmark. jec@cancer.dk
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Adult
Aged
Aged, 80 and over
Breast Neoplasms / genetics,  metabolism*,  pathology*
Carcinoma / genetics,  metabolism,  pathology
Female
Fluorescent Antibody Technique, Direct
Humans
Immunohistochemistry
Keratin-15 / genetics,  metabolism*
Middle Aged
Neoplasm Invasiveness
Precancerous Conditions / chemistry,  pathology*
Stem Cells* / chemistry,  metabolism,  pathology
Chemical
Reg. No./Substance:
0/Keratin-15

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  Use of high density antibody arrays to validate and discover cancer serum biomarkers.
Next Document:  Human papillomavirus is a favourable prognostic factor in tonsillar cancer and its oncogenic role is...