Mammary cancer and epithelial stem cells: a problem or a solution?

Abstract

LacZ = β-galactosidase (Escherichia coli); TGF-β1 = transforming growth factor-beta 1; WAP = whey acidic protein.Available online http://breast-cancer-research.com/content/4/2/047 IntroductionEvidence for mammary epithelial stem cells derives from studies of the glands from rodents, canines and humans. In the human, genetic analysis [1] of contiguous portions of individual human mammary ducts within the same breast signifies their clonal derivation and forecasts the existence of multipotent mammary epithelial cells in the human breast [2][3][4]. This work was confirmed and extended by the demonstration of a common loss of heterozygosity in normal cells in individual lobules within breast tissue from patients with carcinoma, in duct-lobular units from paraffin-embedded mammary tissue, and from normal luminal and myoepithelial cell clones derived from reduction mammoplasty patients [5][6][7].Cell lines from canine mammary spindle-cell tumors exhibited mixed phenotypes on transplantation but possessed identical allelic patterns in microsatellite analysis, suggesting that canine mammary tumors arise from pluripotent stem cells [8].Rat mammary glands contain a subpopulation of clonogenic epithelial cells that, when transplanted, give rise either to alveolar or ductal structures [9]. In quantitative rat mammary cell transplantation studies, both alveolar and ductal colonies were developed that support the conclusion that both colony types are derived from a single clonogenic mammary cell [10,11].In the mouse, it was recently shown that the epithelial population of a fully developed lactating mammary outgrowth in mice could consist of the progeny from a single cell [12]. Serial transplantation of epithelial fragments from the clonally derived gland demonstrated that the subsequently generated outgrowths are also comprised of progeny from the original antecedent. All epithelial cell types were found to be present within these clonal normal populations including luminal, myoepithelial, ductal and lobule-committed epithelial progenitors and fully competent mammary epithelial stem cells. These observations demonstrate the presence of multipotent AbstractThe existing paradigms for stem cells in adult tissues include the integument, the alimentary canal, the lung, the liver, skeletal muscle and bone marrow. The mammary gland, by contrast, is the 'new kid on the block'. What little is known about stem cells in the mammary gland indicates that they possess a prodigious capacity for self-renewal. More importantly, in rodents, they persist with undiminished reproductive vigor throughout the organism's lifetime without regard to age or reproductive history. Do these stem cells represent primary targets for mammary neoplasia? If so, what are the implications for prevention/therapy?

Expression of Terminal Differentiation Proteins Defines Stages of Mouse Mammary Gland Development

“…Consistent with this observation, mammary anlagens develop from PCD 10.5 to PCD 11.5, 34 whereas rudimentary hair follicles in the abdominal area are first detected at PCD13.5-14.5. 41 However, mammary stem cells, which also are the putative origin of mammary tumors, 26,44,50,54 retain some features of follicular stem cells, as indicated by their ability to form tumors with pilar 36,37 and sebaceous (personal observation) differentiation.…”

Genomic analysis of early murine mammary gland development using novel probe-level algorithms

“…For example, the proliferative capacity of small structures in the mammary gland known as terminal end buds gives rise to the extensive ductal structure that is elaborated during puberty [17]. More recently, the characteristics of mammary stem cells have been described, and these cells have been suggested to serve as targets for carcinogenesis [28,29]. To facilitate the study of such subpopulations within a whole-organ context, therefore, we have developed a novel approach to the analysis of Affymetrix oligonucleotide microarray data.…”

The Emerging Picture of Human Breast Cancer as a Stem Cell-based Disease

“…As mentioned above, the first author to propose the existence of BCSCs was Pierce in the 1970s after the identification of low retaining cells in breast tumors [27,28]. Epidemiological studies in populations under radiation, like those from Hiroshima and Nagasaki, indicate that breast cancer develops years or decades after the oncogenic initiation [11,12] and normal stem cells are the only subpopulation of cells that would last long enough to accumulate all the secondary events needed for the acquisition of the complete cancer phenotype [13][14][15][16][17][18]. In summary, these epidemiological and other experimental data suggest that BCSCs might have their origin in the normal mammary stem cells [11,12], but this point is still a matter of controversy, as it is discussed below.…”

“…This small population would generate the more differentiated main mass of the tumor, partially resembling the hierarchical tissue organization of the normal breast. The existence of breast cancer stem cells (BCSCs) is supported by the fact that breast cancer seems to develop decades after the putative oncogenic initiation took place [11,12]; due to the high cellular turnover of the mammary gland, stem cells would be the only subpopulation present in the tissue enough time to accumulate all the oncogenic alterations needed to generate cancer [13][14][15][16][17][18]. These CSCs seem to share a similar phenotype with their normal counterparts, but they display a dysfunctional pattern of proliferation and differentiation, and they no-longer respond to normal physiological controls that ensure a balanced cellular turnover.…”