Common Adult Stem Cells in the Human Breast Give Rise to Glandular and Myoepithelial Cell Lineages: A New Cell Biological Concept

Breast biology and pathology are currently shaped by the two-cell concept that recognizes only glandular and myoepithelial cells. In the present study, we have visualized a previously unidentified cell population within the epithelial compartment of the breast, which displays the phenotypic characteristics of a committed stem cell.Immunofluorescence double labeling with digital image processing and Western blotting were applied to normal breast tissue as well as to noninvasive and invasive breast cancers using antibodies to basal cytokeratin 5 (Ck5), glandular cytokeratins 8/18 (Ck8/18/19), and smooth muscle α-actin (SMA) as markers for myoepithelial cells (SMA).A distinct population of cells was identified that expressed Ck5 in the absence of Ck8/18/19 or SMA. These cells differentiate toward glandular epithelial or myoepithelial Ck5-negative end cells passing through either Ck5/Ck8/18/19 or Ck5/SMA-positive intermediates. Our experiments clearly demonstrate a precursor or committed stem cell function of the Ck5-positive cell that is responsible for regeneration of the human adult breast epithelium. However, the observation that the vast majority of breast cancers display the glandular epithelial immunophenotype strongly suggests that the neoplastic cells derive from a late stage of the glandular epithelial differentiation pathway. The significance of this new cell biological model is that it might serve as a tool to unravel the regulatory mechanisms that govern regeneration and abnormal proliferation of breast epithelium at the cellular level.

[1]  M. Bissell,et al.  Human mammary luminal epithelial cells contain progenitors to myoepithelial cells. , 1999, Developmental biology.

[2]  M. J. van de Vijver,et al.  Ductal carcinoma in situ: a proposal for a new classification. , 1994, Seminars in diagnostic pathology.

[3]  P. Yaswen,et al.  Keratins as markers that distinguish normal and tumor-derived mammary epithelial cells. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[4]  A. Bankfalvi,et al.  Cytokeratin 5/6 immunohistochemistry assists the differential diagnosis of atypical proliferations of the breast , 2000, Histopathology.

[5]  A. Howell,et al.  Dissociation between steroid receptor expression and cell proliferation in the human breast. , 1997, Cancer research.

[6]  S. Schnitt,et al.  MIB‐1 Proliferation Index in Ductal Carcinoma In Situ of the Breast: Relationship to the Expression of the Apoptosis‐Regulating Proteins bcl‐2 and p53 , 2000, The breast journal.

[7]  D. Parmelee,et al.  Separation of cytokeratin polypeptides by gel electrophoretic and chromatographic techniques and their identification by immunoblotting. , 1986, Methods in enzymology.

[8]  Christian A. Rees,et al.  Molecular portraits of human breast tumours , 2000, Nature.

[9]  M. Bissell,et al.  The plasticity of human breast carcinoma cells is more than epithelial to mesenchymal conversion , 2001, Breast Cancer Research.

[10]  J. Sloane,et al.  Abnormal regulation of the oestrogen receptor in benign breast lesions , 2000, Journal of clinical pathology.

[11]  G. Smith,et al.  An entire functional mammary gland may comprise the progeny from a single cell. , 1998, Development.

[12]  S. Lakhani,et al.  The mammary myoepithelial cell - Cinderella or ugly sister? , 2000, Breast Cancer Research.

[13]  G. Raab,et al.  Cell turnover in the "resting" human breast: influence of parity, contraceptive pill, age and laterality. , 1982, British Journal of Cancer.

[14]  R. Dickson,et al.  Genes, oncogenes, and hormones : advances in cellular and molecular biology of breast cancer , 1991 .

[15]  R. Nagle,et al.  Characterization of breast carcinomas by two monoclonal antibodies distinguishing myoepithelial from luminal epithelial cells. , 1986, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[16]  E. Lane,et al.  Antibody markers of basal cells in complex epithelia. , 1990, Journal of cell science.

[17]  R. Moll Cytokeratins as markers of differentiation in the diagnosis of epithelial tumors. , 1998, Sub-cellular biochemistry.

[18]  Benjamin Geiger,et al.  The catalog of human cytokeratins: Patterns of expression in normal epithelia, tumors and cultured cells , 1982, Cell.

[19]  J. Taylor‐Papadimitriou,et al.  Intermediate filament protein expression in normal and malignant human mammary epithelial cells. , 1992, Cancer treatment and research.

[20]  David L. Page,et al.  Diagnostic Histopathology of the Breast , 1988 .

[21]  A. Sonnenberg,et al.  Development of mouse mammary gland: identification of stages in differentiation of luminal and myoepithelial cells using monoclonal antibodies and polyvalent antiserum against keratin. , 1986, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[22]  J. Sloane,et al.  Biopsy pathology of the breast , 1985 .

[23]  M. J. Silverstein,et al.  Prognostic classification of breast ductal carcinoma-in-situ , 1995, The Lancet.

[24]  J. Smith,et al.  Cell proliferation in the human mammary epithelium. Differential contribution by epithelial and myoepithelial cells. , 1986, The American journal of pathology.

[25]  R. Dulbecco,et al.  Marker evolution during the development of the rat mammary gland: stem cells identified by markers and the role of myoepithelial cells. , 1986, Cancer research.

[26]  A. Schermer,et al.  Classification of human epithelia and their neoplasms using monoclonal antibodies to keratins: strategies, applications, and limitations. , 1985, Laboratory investigation; a journal of technical methods and pathology.

[27]  J L Kelsey,et al.  Reproductive factors and breast cancer. , 1993, Epidemiologic reviews.

[28]  D. Craig Allred,et al.  Molecular genetic studies of early breast cancer evolution , 2004, Breast Cancer Research and Treatment.

[29]  B. Ljung,et al.  Ductal lavage for detection of cellular atypia in women at high risk for breast cancer. , 2001, Journal of the National Cancer Institute.

[30]  J. Sloane,et al.  Biopsy Pathology of the Breast (2nd ed.) , 2001 .