DNA methylation inhibitor, procainamide, may decrease the tamoxifen resistance by inducing overexpression of the estrogen receptor beta in breast cancer patients

Abstract 

Estrogen is the main stimulant in the development and growth of breast cancer. The estrogen receptor antagonist tamoxifen has been mainstay of hormonal therapy. Although tamoxifen has been an effective adjuvant therapy, approximately 30% of patients treated with this agent still die within 10 years of follow-up treatment, and relapses can occur for ⩾20 years following therapy. However, the underlying cause of treatment failure in many breast cancer patients receiving tamoxifen is resistance to tamoxifen. ERβ may influence estrogen action through the ERα pathway and the hormone refractoriness of breast cancer. ERβcx, the carboxy terminal splicing variant of ERβ, has been considered a dominant repressor of ERα function, because ERβcx inhibits transcriptional activity of ERα rather than ERβ wild type (wt). Tamoxifen responders tended to exhibit a lower ratio of ERβcx to ERβwt than non-responders. Induction of ERβ reduces growth of exponentially proliferating cells. Since the promoter region of ERβ is rich in CpG dinucleotides, loss of expression of ERβ observed in some tumours could be due to aberrant methylation of CpG islands. Treatment of ERβ-negative cell lines with DNA methyl transferase inhibitors restored ERβ expression, providing experimental evidence that silencing of ERβ in breast carcinomas could be due to promoter hypermethylation. Procainamide, used for cardiac arrhythmias, has been proposed as being a non-nucleoside inhibitor of DNA methylation and also demthylates and reactivate tumor suppressor genes in breast cancer cell lines. Therefore, concomitant use of procainamide with tamoxifen in ERα-positive and ERβ-negative breast cancers may increase the tamoxifen response. Procainamide, given orally may also be used in breast cancer patients who developed resistance during the tamoxifen treatment. In vivo and in vitro studies evaluating effectiveness of concomitant use of procainamide and tamoxifen in tamoxifen resistant and ERβ-negative breast cancer may further support our hypothesis.