Epigenetic mechanisms play crucial roles in many processes, including neoplasia, genomic imprinting, gene silencing, differentiation, embryogenesis and X chromosome inactivation. Their relevance in human disease and therapy has grown rapidly with the recent emergence of drugs that target for example DNA methylation or histone acetylation. Epigenetic effects were also recently highlighted by the deciphering of the mechanism of action of steroid hormones and anti-hormones acting through nuclear receptors. In this review, we focus on the epigenetic effects associated with long-term treatment of breast cancer cells with the antiestrogen (AE) tamoxifen, in the context of resistance appearance. We summarize the data obtained with a model cell line developed in our laboratory supporting a role for HP1 proteins in the irreversible inactivation of gene expression by long-term treatment with AE.

In previous studies, microarray analysis of livers from mice fed diethyl-1,4-dihydro-2,4,6-trimethyl-3,5-pyridine decarboxylate (DDC) for 10 weeks followed by 1 month of drug withdrawal (drug-primed mice) and then 7 days of drug refeeding showed an increase in the expression of numerous genes referred to here as the molecular cellular memory. This memory predisposes the liver to Mallory Denk body formation in response to drug refeeding. In the current study, drug-primed mice were refed DDC with or without a daily dose of S-adenosylmethionine (SAMe; 4 g/kg of body weight). The livers were studied for evidence of oxidative stress and changes in gene expression with microarray analysis. SAMe prevented Mallory Denk body formation in vivo . The molecular cellular memory induced by DDC refeeding lasted for 4 months after drug withdrawal and was not manifest when SAMe was added to the diet in the in vivo experiment. Liver cells from drug-primed mice spontaneously formed Mallory Denk bodies in primary tissue cultures. SAMe prevented Mallory Denk bodies when it was added to the culture medium. Conclusion: SAMe treatment prevented Mallory Denk body formation in vivo and in vitro by preventing the expression of a molecular cellular memory induced by prior DDC feeding. No evidence for the involvement of oxidative stress in induction of the memory was found. The molecular memory included the up-regulation of the expression of genes associated with the development of liver cell preneoplasia. (Hepatology 2007.) ( This is a corrected version of the abstract first published online on 20 December 2007 — the corrected version appears in print. )