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

Abstract

SUMMARY: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 ␣-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. (Lab Invest 2002, 82:737-745).

KIT is highly expressed in adenoid cystic carcinoma of the breast, a basal-like carcinoma associated with a favorable outcome

“…In solid areas, p63-positive cells were predominant. By classifying breast cell populations according to the system proposed by Bocker, 36 we identified four distinct types of cells in adenoid cystic carcinoma of the breast; rare CK5/6 þ cells (CK8/18À/p63À) or progenitor cells, CK5/6 þ /CK8/18 þ cells (/p63À) or glandular precursor cells, CK8/18 þ cells Although the origin of adenoid cystic carcinoma of the breast is still debated, it seems to be widely accepted that this tumor is derived from undifferentiated cells, which have the capacity to differentiate towards ductal and myoepithelial cells. 9,10,25,37 Our study confirmed this theory, as we demonstrated the presence of CK5/6 þ cells that could represent precursor cells.…”

“…Nonsentinel axillary lymph node dissection was performed in Adenoid cystic carcinoma of the breast S Azoulay et al eight cases. The median number of lymph nodes examined was 12 (range: [7][8][9][10][11][12][13][14][15][16][17][18][19]. No lymph node metastases were seen in either of these cases.…”

“…Therefore, five distinct cell populations have been identified within the mammary gland: committed stem cell (CK5/6 þ ), glandular precursor cell (CK5/6 þ , CK8/ 18 þ ), glandular end cell (CK8/18 þ ), myoepithelial precursor cell (CK5/6 þ ) and myoepithelial cells. 12 To investigate this new biological concept in adenoid cystic carcinoma of the breast, we examined the expression of CK8/18, CK5/6, and p63 (as a myoepithelial marker) 13 in a series of 18 adenoid cystic carcinomas of the breast. Moreover, recent studies have revealed that KIT (CD117), a transmembrane tyrosine kinase receptor encoded by the protooncogene c-KIT, is expressed in 90% of adenoid cystic carcinomas of the salivary gland but not in normal salivary gland tissue or other head and neck neoplasms.…”

K5/K14-positive cells contribute to salivary gland-like breast tumors with myoepithelial differentiation

“…Both glands contain K5/K14/p63-positive progenitor cells, which give rise to glandular cells with subsequent downregulation of basal keratins/p63 and upregulation of glandular keratins K7/K8/18. Furthermore, it has been demonstrated for breast tissue that the myoepithelial cells originate (embryologically, in transplantation studies, and during physiological regeneration) from K5 and/or K14-positive progenitors 52,53,55 that co-express p63. 16 Our isTILT data provide support for similar cellular differentiation processes in the salivary gland (Boecker et al, manuscript in preparation).…”

Characterization of a novel anti-fatty acid synthase (FASN) antiserum in breast tissue

“…Many markers have been postulated to identify breast stem/progenitor cells in both the luminal and myoepithelial compartments. [20][21][22][23][24][25][26] Our experience with one of these putative stem cell markers, CK5/6, 21 is that its expression in normal breast is typically seen in a continuous portion of the basal epithelial compartment, suggesting a myoepithelial expression phenotype. Other authors have provided some evidence that CK5/6 reactivity may not, indeed, represent a stem cell phenotype.…”