DNMT1 has prognostic values in HER2-positive breast cancer

Abstract

Abstract Background: Interleukin-6 (IL-6) was found to induce aberrant methylation in critical genes involved in insulin signaling and angiogenesis in humans, presumably due to protein stabilization of DNA methyltransferases. Whether IL-6 and DNMT1 impact breast cancer (BC) prognosis remains unknown. Methods TIMER2.0 web server was used for comprehensive analysis from TCGA. Associations between DNMT1 and IL-6 in tumor immune microenvironment was explored via single cell sequencing (SCS) from TISCH. IL-6 and DNMT1 expressions were investigated in tissue microarray of our own cohort (n = 285) as well as in BC cell-lines. Invasion activity was compared between high and low IL-6/DNMT expressing BC cell-lines treated with/without IL-6 antibody. Results DNMT1 mRNA was significantly higher in the BC tissues (p < 0.001) with a mutation rate of 1.16%. A positive correlation between IL-6 and DNMT1 protein levels was found in tissue array. Increased IL-6 mRNA did not appear to be a good prognostic marker for overall survival in HER2 + BC patients whereas higher DNMT1 mRNA was a good prognostic marker for poor overall survival in HER2 + BC patients. Among different BC subtypes in our cohort, hormone receptor negative (HR-)/HER2 positive (HER2+) patients had the poorest survival (n = 43). Cox regression indicated that IL-6, and DNMT1 are independent prognostic factors in HR-/HER2 + BC patients. DNMT1 expressed in malignant cells, also in innate and adaptive immune cells including macrophages, CD4(+)T and CD8(+)T cells, whereas IL-6 was only found in malignant cells. HER2 + MDA-MB-453 (high IL-6/high DNMT1) exhibited higher invasiveness compared to HER2 + SKBR3 (low IL-6/low DNMT1). IL-6 (10 ng/ml) significantly promoted the invasiveness in SKBR3 whereas IL-6 antibody (10 µg/ml) significantly suppressed the invasiveness of MDA-MB-453. Conclusions DNMT1 overexpression could be responsible for HR-/HER2 + BC progression in tumor immune microenvironment. We suggest that IL-6 inhibition in combination with anti-HER2 therapy is a potential therapeutic strategy for treating DNMT1-overexpressing HER2-positive BC patients.