Culture models of human mammary epithelial cell transformation

Human pre-malignant breast diseases, particularly ductal carcinoma in situ (DCIS)(3) already display several of the aberrant phenotypes found in prima ry breast cancers, including chromosomal abnormalities, telomerase activity , inactivation of the p53 gene, and overexpression of some oncogenes. Effor ts to model early breast carcinogenesis in human cell cultures have largely involved studies of in vitro transformation of normal finite lifespan huma n mammary epithelial cells (HMEC) to immortality and malignancy. We present a model of HMEC immortal transformation consistent with the known in vivo data. This model includes a recently described, presumably epigenetic proce ss, termed conversion, which occurs in cells that have overcome stringent r eplicative senescence and are thus able to maintain proliferation with crit ically short telomeres. The conversion process involves reactivation of tel omerase activity, and acquisition of good uniform growth in the absence and presence of TGF beta. We propose that overcoming the proliferative constra ints set by senescence, and undergoing conversion, represent key rate-limit ing steps in human breast carcinogenesis, and occur during early stage brea st cancer progression.