PURPOSE

Emerging evidence suggests that cytotoxic therapy may promote drug resistance and metastasis while inhibiting the growth of primary tumors. As yet, however, the underlying mechanisms remain unclear. Here, we aimed to investigate the pro-metastatic effects of adriamycin (ADR) therapy on breast cancer cells and to investigate the mechanisms underlying these effects.

METHODS

Differentially expressed genes between MCF-7 and ADR-resistant MCF-7 breast cancer cells were identified using high-throughput RNA-seq and differential gene expression analyses. In vitro transwell and scratch wound-healing assays, and an in vivo spontaneous metastasis model were used to study the metastatic potential of the breast cancer cells. The relationship between SIRT7 and TEK expression was studied using promoter activity, electrophoretic mobility shift (EMSA), CHIP-qPCR and Co-IP assays.

RESULTS

Using transcriptome sequencing, we identified two key genes (SIRT7 and TEK) that might contribute to the pro-metastatic effect of ADR on breast cancer cells. SIRT7 acted as a negative regulator for TEK by inducing deacetylation of H3K18 at the TEK promoter. Through transcription factor prediction and double fluorescence experiments, we found that EST-1 could bind to the TEK promoter. Knockdown of EST-1 removed the transcriptional inhibition of TEK that was mediated by up-regulation of SIRT7. Co-IP showed that SIRT7 interacts directly with EST-1 in breast cancer cells, indicating that SIRT7 may induce H3K18 deacetylation at the TEK promoter region by directly binding to EST-1. In vitro and in vivo results showed that overexpression of SIRT7 or inhibition of TIE2 significantly reduced ADR-dependent breast cancer cell invasion/metastasis.

CONCLUSION

Our findings suggest that ADR therapy may accelerate breast cancer metastasis in a SIRT7/TEK(TIE2) dependent manner.