Abstract
The adult human breast gland consists of a branched system of ducts and ductules essentially composed of an inner layer of luminal epithelial cells expressing keratins of simple epithelia and an outer layer of myoepithelial cells expressing keratins of stratified epithelia and a range of contractile filaments. With a view to understanding why some breast carcinomas appear as either basal-like, bimodal or stem cell-derived and others as strictly luminal epithelial-like, we set out to elucidate whether a hierarchy of epithelial differentiation could be demonstrated within the lineages of the human breast gland. For that purpose we have used primary cultures from reduction mammoplasties, immunomagnetic cell sorting and a set of markers for each of the major two lineages. Our initial observations on sorted primary cultures led to the conclusion that myoepithelial cells were lineage restricted in their differentiation repertoire while a subset of cells within the luminal epithelial lineage could convert to myoepithelial cells. Next, we included a three-dimensional reconstituted basement membrane assay in which luminal epithelial cells essentially formed spherical acinus-like structures while myoepithelial cells formed larger solid balls. In an effort to enrich for cells with a broader morphogenic potential we isolated and immortalized a cell type intermediate between luminal and myoepithelial cells, which could make relatively elaborate terminal duct-like structures and organize layers of both luminal-like and myoepithelial-like cells. Currently, we are expanding on our panel of cloned cell lines with normal cellular equivalents in situ as determined by immunochemical portraying. These cell lines are now being tested for their plasticity in culture to further approach a tentative hierarchical scheme for breast epithelial differentiation.
Highlights
The remarkable generation of scores of increasingly sophisticated mouse models of mammary cancer over the past two decades has provided tremendous insights into molecular derangements that can lead to cancer
We report that somatic mutations of p53 in mouse mammary epithelial cells lead to ERα-positive and ERαnegative tumors. p53 inactivation in pre-pubertal/pubertal mice, but not in adult mice, leads to the development of ERα-positive tumors, suggesting that developmental stages influence the availability of ERα-positive tumor origin cells
Genetic alterations commonly observed in human breast cancer including c-myc amplification and Her2/Neu/erbB2 activation were seen in these mouse tumors
Summary
Transgenic Oncogenesis Group, Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, Bethesda, Maryland, USA. The remarkable generation of scores of increasingly sophisticated mouse models of mammary cancer over the past two decades has provided tremendous insights into molecular derangements that can lead to cancer. The relationships of these models to human breast cancer, remain problematic. P53 inactivation in pre-pubertal/pubertal mice, but not in adult mice, leads to the development of ERα-positive tumors, suggesting that developmental stages influence the availability of ERα-positive tumor origin cells. These tumors have a high rate of metastasis that is independent of tumor latency. Since it is feasible to isolate ERα-positive epithelial cells from normal mammary glands and tumors, molecular mechanisms underlying ERα-positive and ERα-negative mammary carcinogenesis can be systematically addressed using this model
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