Expression and clinicopathological significance of DNA methyltransferase 1, 3A and 3B in tamoxifen-treated breast cancer patients

Abstract

Progression of tamoxifen resistance remained as a crucial obstacle to treatment of estrogen receptor positive breast carcinoma patients. Recent studies demonstrated the importance of DNA methylation pattern on tamoxifen refractory. This study aimed to investigate the protein expression pattern and clinicopathological significance of DNA methyltransferase 1, 3A and 3B, as leading factors in regulation of DNA methylation process, in breast carcinoma patients with adjuvant tamoxifen therapy. Seventy two Formalin-Fixed Paraffin-Embedded (FFPE) breast tumor tissues of tamoxifen sensitive (TAMS) and tamoxifen resistance (TAM-R) patients were recruited for immunohistochemical experiments. DNMT1, DNMT3a, and DNMT3b expressions were observed in 86, 72.2 and 100% of tamoxifen resistance patients, respectively. Data analysis indicated that DNMTs were overexpressed in TAM-R tumors (P < 0.05). In TAM-S subgroup, DNMT1, DNMT3A and DNMT3B expression was associated with high histologic grade (P = 0.049, P = 0.01 and P = 0.02, respectively). DNMT3B expression was also correlated with lymphatic invasion (P = 0.034). In TAM-R subgroup, DNMT1 expression associated with extracapsular nodal extension (P = 0.019). DNMT3A and DNMT3B expression showed a significant association with high histologic grade (P = 0.001) and DNMT3A expression was also associated with HER-2 status (P = 0.027). Cox proportional hazard model demonstrated that overexpression of DNMT3B remained as an independent and unfavorable prognostic factor for disease free survival (P < 0.001). Taken together, these results suggest that DNMTs could be an effective factor in development of tamoxifen resistance in breast tumors.