RAR Beta Methylation and Loss of RAR Beta Expression in Breast Cancer
Annual rept. 1 Sep 1999-31 Aug 2000
JOHNS HOPKINS UNIV BALTIMORE MD SCHOOLOF MEDICINE
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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 RAR beta was reported in breast cancer, as well as in other epithelial cancers. Our IDEA project aims to understand the mechanisms involved in RAR 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 RAR beta loss in breast cancer cells. Moreover, we found that relieving chromatin repression, by either demethylation or reacetylation at RAR beta promoter level, can restore RAR beta expression. Now, we plan to test whether loss of RAR beta expression can be prevented in breast cells by maintaining an appropriate activity of the RAR beta P2 promoter to deter the occurrence of epigenetic events that now we know are responsible for RAR beta silencing and RA-resistance.
- Anatomy and Physiology
- Medicine and Medical Research