Epigenetic changes accompanying human mammary epithelial cell immortalization.

Acquisition of immortality may be an early and crucial step in malignant progression. We hypothesize that acquisition of unlimited growth potential in individual human mammary epithelial cells (HMEC) requires inactivation of several distinct negative growth constraints as well as reactivation of a mechanism to maintain telomeres on chromosomes. Some of the heritable changes that occur during HMEC immortalization, i.e., loss of expression of cyclin dependent kinase inhibitors p16INK4a and p57KIP2, loss of TGFbeta-mediated growth inhibition, and derepression of telomerase, appear to occur without identifiable mutations in the genes and pathways involved. The absence of mutations, combined with the fact that the changes are often incremental over several cell generations even in clonal populations indicates that some changes associated with immortalization can be epigenetic. We have used the term "conversion" to describe the gradual epigenetic process in chemical carcinogen-immortalized HMEC that leads to activation of telomerase, stabilization of telomere length, and ability to grow uniformly well in the presence or absence of TGFbeta. Characterization of the epigenetic mechanisms involved in immortalization may uncover additional factors that drive tumor progression, and that may be responsive to novel forms of intervention.