The Role of Stem Cell in Breast Cancer Prevention

Abstract

Stem cells in adult structures have been defined by their ability for self-renewal and for generating a differentiated progeny. In the mammary gland, Deome et al. [1] demonstrated that fragments of different parenchymal portions were able to generate fully functional mammary outgrowths in mice, forming ductal and lobuloalveolar structures composed by epithelial and myoepithelial cells. This concept was further developed by Kordon and Smith [2] who demonstrated that the progeny from a single cell might comprise the epithelial population of a fully developed lactating mammary outgrowth in mice. Thus, the development of the complete mammary tree from a small portion of a duct or from single cells attests of their multifaceted potential. However, it was not known whether these progenitor/stem cells would be capable of initiating cancer when exposed to a carcinogenic agent. This issue was addressed by Russo and coworkers [3–5], who demonstrated that cancer, started in terminal end buds (TEBs) present in the mammary gland of young virgin rats. The analysis of these structures by electron microscopy allowed them to characterize their cellular composition based upon cell and nuclear size, nuclear-cytoplasmic ratio, amount of chromatin condensation, electron density of the cytoplasm, number and distribution of organelles, and the presence or absence of Mg2+ and Na+K+-dependent ATPases. Based upon these criteria, in addition to myoepithelial cells, three types of epithelial cells were identified: Light, intermediate, and dark cells [4, 5]. Dark cells were found to be the predominant type in TEBs; intermediate and myoepithelial cells were present in significantly lower percentages and light cells were only occasionally seen; therefore, their percentage was combined with that of intermediate cells. The analysis of the DNA labeling index revealed that all the cell types proliferated, although at different rates, depending upon the type of cells and of their location within the mammary gland tree. Cell proliferation was maximal in intermediate cells located in TEBs, being significantly lower in dark and myoepithelial cells found in the same location. High cell proliferation was associated with greater incorporation of H3-DMBA, and a progressive dominance of intermediate cells in DMBA-induced intraductal proliferations (IDPs) and in ductal carcinomas [5, 6]. These results indicated that intermediate cells were not only the targets of the carcinogen but also the stem cells of mammary carcinomas. Further work by Bennett et al. [7] demonstrated that intermediate cells isolated from DMBA-induced mammary tumors originated two cell types in culture, the dark cell, representing a terminally differentiated cell or a class in transition to differentiation, and intermediate cells, which could represent an undifferentiated, or stem cell, a progenitor of dark and myoepithelial cells. Rudland et al. [8] isolated and characterized from the normal rat mammary gland and from DMBA-induced mammary adenocarcinomas epithelial cells that were cuboidal and gave rise to a mixture of cuboidal and spindle-shaped cells resembling fibroblasts. In confluent cultures, cuboidal cells acquired the morphology of a third type of cells, which were dark, polygonal, and with many small vacuoles, resembling the dark cells ultrastructurally described by Russo et al. [5]. Chepko and Smith [9] differentiated three division-competent cell populations in the murine mammary epithelium, a subset of “large light cells” structurally and functionally compatible with early stages of secretory differentiation, “small light cells” that were the least differentiated, suggesting that the large light cells were a direct precursor to terminally differentiated cells, both secretory and myoepithelial. These results confirmed the Russo’s work [5].