Altundag Ozden, Altundag Kadri, Gunduz Mehmet
Department of Medical Oncology, Institute of Oncology, Faculty of Medicine, Hacettepe University, Sihhiye, 06100 Ankara, Turkey.
Med Hypotheses. 2004;63(4):684-7. doi: 10.1016/j.mehy.2004.03.017.
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 > or = 20 years following therapy. However, the underlying cause of treatment failure in many breast cancer patients receiving tamoxifen is resistance to tamoxifen. ERbeta may influence estrogen action through the ERalpha pathway and the hormone refractoriness of breast cancer. ERbetacx, the carboxy terminal splicing variant of ERbeta, has been considered a dominant repressor of ERalpha function, because ERbetacx inhibits transcriptional activity of ERalpha rather than ERbeta wild type (wt). Tamoxifen responders tended to exhibit a lower ratio of ERbetacx to ERbetawt than non-responders. Induction of ERbeta reduces growth of exponentially proliferating cells. Since the promoter region of ERbeta is rich in CpG dinucleotides, loss of expression of ERbeta observed in some tumours could be due to aberrant methylation of CpG islands. Treatment of ERbeta-negative cell lines with DNA methyl transferase inhibitors restored ERbeta expression, providing experimental evidence that silencing of ERbeta 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 ERalpha-positive and ERbeta-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 ERbeta-negative breast cancer may further support our hypothesis.
雌激素是乳腺癌发生和发展的主要刺激因素。雌激素受体拮抗剂他莫昔芬一直是激素治疗的主要药物。尽管他莫昔芬是一种有效的辅助治疗药物，但接受该药物治疗的患者中约有30%在后续治疗的10年内仍会死亡，且治疗后20年或更长时间可能会复发。然而，许多接受他莫昔芬治疗的乳腺癌患者治疗失败的根本原因是对他莫昔芬耐药。雌激素受体β（ERβ）可能通过雌激素受体α（ERα）途径影响雌激素作用以及乳腺癌的激素难治性。ERβ的羧基末端剪接变体ERβcx被认为是ERα功能的主要抑制因子，因为ERβcx抑制ERα而非ERβ野生型（wt）的转录活性。他莫昔芬反应者的ERβcx与ERβwt的比例往往低于无反应者。ERβ的诱导可减少指数增殖细胞的生长。由于ERβ的启动子区域富含CpG二核苷酸，在一些肿瘤中观察到的ERβ表达缺失可能是由于CpG岛的异常甲基化。用DNA甲基转移酶抑制剂处理ERβ阴性细胞系可恢复ERβ表达，这提供了实验证据表明乳腺癌中ERβ的沉默可能是由于启动子高甲基化。用于治疗心律失常的普鲁卡因酰胺被认为是一种DNA甲基化的非核苷抑制剂，它还能使乳腺癌细胞系中的肿瘤抑制基因去甲基化并重新激活。因此，在ERα阳性和ERβ阴性乳腺癌中，将普鲁卡因酰胺与他莫昔芬联合使用可能会增加他莫昔芬的反应。口服的普鲁卡因酰胺也可用于在他莫昔芬治疗期间产生耐药性的乳腺癌患者。评估普鲁卡因酰胺和他莫昔芬联合使用对他莫昔芬耐药和ERβ阴性乳腺癌有效性的体内和体外研究可能会进一步支持我们的假设。
