RAR Beta Methylation and Loss of RAR Beta Expression in Breast Cancer

摘要

The search of chemopreventive strategies for breast cancer is imperative. It is vital to identify critical early events that can increase the risk that a normal epithelial mammary cell may be transformed into a breast cancer cell. Exposure to estrogen, already, recognized as a predisposing event for breast cancer, formed the rationale for preventive trials based on an antiestrogen compound (tamoxifen). This proposal explores the mechanism of another likely predisposing event for breast cancer, the loss of expression of the retinoic acid receptor beta (RAR beta), a nuclear receptor that responds to derivatives of vitamin A. Loss of expression of EAR beta was reported in breast cancer, as well as in other epithelial cancers. Our IDEA project aims to understand the mechanisms involved in EAR beta loss, in order to devise strategies not only to reverse this loss, but also to prevent it. In the first year of investigation, we found that a mechanism of transcriptional silencing of genes called hypermethylation is an important factor of irreversible EAR beta loss in breast cancer cells. In the second year we tested in depth the epigenetic mechanisms (deacetylation of P2) leading to downregulation and loss of EAR beta expression and development of RA resistance. This paves the road to a) treatment of RA-resistant breast cancer and 2) chemoprevention of breast cancer by maintaining an appropriate activity of the EAR beta P2 promoter to deter the occurrence of epigenetic events responsible for EAR beta silencing and RA-resistance.