The association of aging with increased incidence of breast cancer is well known, but little understood. Emphasis has been placed on differences among tumors as a function of age, while considerably less attention is given to changes that occur normally in mammary epithelium during the process of aging, which may facilitate tumor genesis. Studying a unique collection of cultured strains of normal pre-stasis finite lifespan human mammary epithelial cells generated from over 47 different women we have identified fundamental changes to the mammary epithelium that take place during aging. Contrary to expectations, aging was associated with increases in the proportional size of a cKit-expressing progenitor pool, which acquired differentiation defects, thus giving rise to luminal epithelial cels that expressed proteins normally associated with myoepithelial cells in younger women; and fewer myoepithelial cells were generated. Myoepithelial cells are putatively tumor- suppressive, and progenitors are putative etiological roots of some breast cancers. Thus during the aging process the population of cells potentially targeted for transformation is increased and there is a simultaneous decrease in tumor suppressive cells, which suggests a cellular mechanism that leads to increased vulnerability to malignant progression. We were able to draw these conclusions by correlating results of in vitro cell-based functional assays on flow cytometry enriched subsets with observations of tissues in vivo. Indeed, the developmental lineage hierarchy of human mammary epithelia as we know it has been elucidated using many of the same functional assays and work flows. Whereas that approach is excellent for proving connectedness of one subset to another, it is inefficient and difficult to identify heretofore-unknown lineages and intermediates. Here we propose to utilize a new high-dimensional cytometry method to perform lineage tracing by deep profiling as a function of age in a large collection of primary uncultured human mammary epithelia. The expected outcome of this work will be elucidation, at unprecedented detail, of age-dependent changes in lineage hierarchies in primary human mammary epithelia, and characterization of the stroma adjacent to the gland. The proposed work will positively impact the aging and cancer fields by providing a basic understanding of the progenitors and differentiated lineages that are most altered by aging. As gene expression profiling is performed on newly identified age- affected intermediates in the lineage hierarchy, we will begin to identify specific associated molecular changes, which will serve as potential early intervention, prophylaxis, and prevention targets.
It has been known for decades that aging is one of the principle risk factors for breast cancer; yet the impact of the normal aging process on function and architecture of normal breast epithelium is not well characterized. This proposal uses unique biological and technological assets that were developed at the Lawrence Berkeley National Laboratory to generate a previously unrealizable atlas of functional and architectural changes that occur during the process of aging. We will identify normal age- associated changes that may create a predisposition towards malignant states when combined with additional genetic mutations; with a goal of informing future prophylactic or preventative strategies.
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