TY - JOUR
T1 - Identification of a subset of breast carcinomas characterized by expression of cytokeratin 15
T2 - Relationship between CK15+ progenitor/amplified cells and pre-malignant lesions and invasive disease
AU - Celis, Julio E.
AU - Gromova, Irina
AU - Cabezón, Teresa
AU - Gromov, Pavel
AU - Shen, Tao
AU - Timmermans-Wielenga, Vera
AU - Rank, Fritz
AU - Moreira, José M.A.
PY - 2007/1/1
Y1 - 2007/1/1
N2 - 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.
AB - 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.
KW - Breast cancer
KW - CK15
KW - Progenitor cells
KW - Proteomics
KW - Tumour heterogeneity
KW - Tumour subtypes
UR - http://www.scopus.com/inward/record.url?scp=36549018964&partnerID=8YFLogxK
U2 - 10.1016/j.molonc.2007.09.004
DO - 10.1016/j.molonc.2007.09.004
M3 - Journal article
AN - SCOPUS:36549018964
SN - 1574-7891
VL - 1
SP - 321
EP - 349
JO - Molecular Oncology
JF - Molecular Oncology
IS - 3
ER -
