Epigenetic downregulation of the retinoic acid receptor-beta 2 gene in breast cancer

A growing body of evidence supports the hypothesis that the retinoic acid r eceptor,beta2 (RAR-beta2)(3) gene is a tumor suppressor gene which induces apoptosis and that the chemopreventive and therapeutic effects of retinoids are due to induction of RAR-beta2. During breast cancer progression, RAR-b eta2 is reduced or even lost. It is known from studies of other tumor-suppr essor genes that methylation of the 5'-region is the cause of loss of expre ssion. Several groups demonstrated that this is also true for the RAR-beta2 in breast cancer by treating breast cancer cell lines with a demethylating agent and examining expression of the RAR-beta2 gene in response to a chal lenge with retinoic acid. Studies using sodium bisulfite genomic sequencing as well as methylation specific PCR showed that a number of breast cancer cell lines as well as breast cancer tissue showed signs of methylation. The RAR-beta2 gene was unmethylated in non-neoplastic breast tissue as well as in other normal tissues. A combination of retinoic acid with demethylating agents as well as with histone deacetylase inhibitors acts synergistically to inhibit growth. This review presents data that suggest that treatment o f cancer patients with demethylating agents followed by retinoic acid may o ffer a new therapeutic modality. Both the time of commencement of chemoprev ention and the choice of substances that are able either to prevent de novo methylation or to reverse methylation-caused gene silencing may be importa nt considerations.