Women over 50 years of age account for 75% of new breast cancer diagnoses, and the majority of these tumors are of a luminal subtype. Although age-associated changes, including endocrine profiles and alterations within the breast microenvironment, increase cancer risk, an understanding of the molecular mechanisms that underlie these observations is lacking. In this study, we generated a large collection of normal human mammary epithelial cell strains from women aged 16 to 91 years, derived from primary tissues, to investigate the molecular changes that occur in aging breast cells. We found that in finite-lifespan cultured and uncultured epithelial cells, aging is associated with a reduction of myoepithelial cells and an increase in luminal cells that express keratin 14 and integrin α6, a phenotype that is usually expressed exclusively in myoepithelial cells in women under 30. Changes to the luminal lineage resulted from age-dependent expansion of defective multipotent progenitors that gave rise to incompletely differentiated luminal or myoepithelial cells. The aging process therefore results in both a shift in the balance of luminal/myoepithelial lineages and to changes in the functional spectrum of multipotent progenitors, which together increase the potential for malignant transformation. Together, our findings provide a cellular basis to explain the observed vulnerability to breast cancer that increases with age.
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