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

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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. / Celis, Julio E.; Gromova, Irina; Cabezón, Teresa; Gromov, Pavel; Shen, Tao; Timmermans-Wielenga, Vera; Rank, Fritz; Moreira, José M.A.

In: Molecular Oncology, Vol. 1, No. 3, 01.01.2007, p. 321-349.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Celis, JE, Gromova, I, Cabezón, T, Gromov, P, Shen, T, Timmermans-Wielenga, V, Rank, F & Moreira, JMA 2007, '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', Molecular Oncology, vol. 1, no. 3, pp. 321-349. https://doi.org/10.1016/j.molonc.2007.09.004

APA

Celis, J. E., Gromova, I., Cabezón, T., Gromov, P., Shen, T., Timmermans-Wielenga, V., Rank, F., & Moreira, J. M. A. (2007). 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. Molecular Oncology, 1(3), 321-349. https://doi.org/10.1016/j.molonc.2007.09.004

Vancouver

Celis JE, Gromova I, Cabezón T, Gromov P, Shen T, Timmermans-Wielenga V et al. 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. Molecular Oncology. 2007 Jan 1;1(3):321-349. https://doi.org/10.1016/j.molonc.2007.09.004

Author

Celis, Julio E. ; Gromova, Irina ; Cabezón, Teresa ; Gromov, Pavel ; Shen, Tao ; Timmermans-Wielenga, Vera ; Rank, Fritz ; Moreira, José M.A. / 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. In: Molecular Oncology. 2007 ; Vol. 1, No. 3. pp. 321-349.

Bibtex

@article{f0d45f338160417f83853a3172c103c3,
title = "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",
abstract = "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.",
keywords = "Breast cancer, CK15, Progenitor cells, Proteomics, Tumour heterogeneity, Tumour subtypes",
author = "Celis, {Julio E.} and Irina Gromova and Teresa Cabez{\'o}n and Pavel Gromov and Tao Shen and Vera Timmermans-Wielenga and Fritz Rank and Moreira, {Jos{\'e} M.A.}",
year = "2007",
month = jan,
day = "1",
doi = "10.1016/j.molonc.2007.09.004",
language = "English",
volume = "1",
pages = "321--349",
journal = "Molecular Oncology",
issn = "1574-7891",
publisher = "Elsevier",
number = "3",

}

RIS

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

VL - 1

SP - 321

EP - 349

JO - Molecular Oncology

JF - Molecular Oncology

SN - 1574-7891

IS - 3

ER -

ID: 221777814