Epigenetic changes accompanying human mammary epithelial cell immortalization

Acquisition of immortality may be an early and crucial step in malignant pr ogression. We hypothesize that acquisition of unlimited growth potential in individual human mammary epithelial cells (HMEC)(3) requires inactivation of several distinct negative growth constraints as well as reactivation of a mechanism to maintain telomeres on chromosomes. Some of the heritable cha nges that occur during HMEC immortalization, i.e., loss of expression of cy clin dependent kinase inhibitors p16(INK4a) and p57(KIP2), loss of TGF beta -mediated growth inhibition, and derepression of telomerase, appear to occ ur without identifiable mutations in the genes and pathways involved. The a bsence of mutations, combined with the fact that the changes are often incr emental over several cell generations even in clonal populations indicates that some changes associated with immortalization can be epigenetic. We hav e used the term "conversion" to describe the gradual epigenetic process in chemical carcinogen-immortalized HMEC that leads to activation of telomeras e, stabilization of telomere length, and ability to grow uniformly well in the presence or absence of TGF beta. Characterization of the epigenetic mec hanisms involved in immortalization may uncover additional factors that dri ve tumor progression, and that may be responsive to novel forms of interven tion.