More than 90% of human cancers are of epithelial origin. Cellular senescence of human mammary epithelial cells (HMECs) is an important barrier that protects cells from immortalization; the first step in breast cancer development. Although induction of tumor suppressor p16 is not evident in some types of normal human fibroblasts undergoing senescence, in cultured HMECs, senescence occurs by a robust p16 induction, and cells that acquire silencing of p16lnk4a locus eventually proliferate and undergo senescence again by telomere shortening in a p53-dependent manner. Therefore, p16 induction is a critical barrier to immortalize HMECs in culture. p16 inhibits kinase activity of Cdk4/6-cyclinD complexes, which inactivate three pRb family proteins: pRb, p107 and p130. However, the relative contribution of these three pRb family proteins to HMEC senescence is not well understood.
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