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We have previously identified a rare subpopulation of variant human mammary epithelial cells (vHMEC) with repressed p16 INK4A  that exist in disease-free women yet display premalignant properties, suggesting that they have engaged the process of malignant transformation. In order to gain insight into the molecular alterations required for vHMEC to progress to malignancy, and to characterize the epigenetic events associated with early progression, we examined the effect of oncogenic stress on the behavior of these cells.    Methods  HMEC that express p16 INK4A  and vHMEC that do not, were transduced with constitutively active Ha-rasV12 and subsequently exposed to serum to determine whether signals from the cellular microenvironment could cooperate with ras to promote the malignant transformation of vHMEC. Epigenetic alterations were assessed using methylation-specific polymerase chain reaction (PCR).    Results  vHMEC expressing Ha-rasV12 (vHMEC-ras) bypassed the classic proliferative arrest that has been previously documented in normal fibroblasts following oncogenic stress, and that we also observe here in normal HMEC. Moreover, vHMEC-ras cells exhibited many additional alterations that are observed during progression to malignancy such as the generation of chromosomal abnormalities, upregulation of telomerase activity, immortalization following exposure to serum, and anchorage-independent growth, but they did not form tumors following orthotopic injection  in vivo . Associated with their early progression to malignancy was an increase in the number of genes methylated, two of which ( RASSF1A  and  SFRP1 ) were also methylated in other immortalized mammary cell lines as well as in breast cancer cells and tissues.    Conclusions  We have characterized a mammary progression model that recapitulates molecular and methylation alterations observed in many breast cancers. Our data suggest that concomitant methylation of  RASSF1A  and  SFRP1  marks an early event in mammary transformation and may thus have prognostic potential.

Human mammary cancer progression model recapitulates methylation events associated with breast premalignancy