# Synergistic Reduction of Breast Cancer Cell Viability and Aggressiveness Through Dual Inhibition of APE1 Redox Function and STAT3 Signaling

## TL;DR

This study shows that combining inhibitors of APE1 and STAT3 can reduce breast cancer cell survival and aggressiveness, suggesting a new treatment strategy.

## Contribution

The study first reports the synergistic effect of dual inhibition of APE1 redox function and STAT3 in breast cancer.

## Key findings

- Combined treatment with APE1 and STAT3 inhibitors reduces cell viability, proliferation, migration, and invasion more than single treatments.
- APE1 and STAT3 activity levels correlate with proliferation and metastasis gene signatures in breast cancer.
- APX2009 impairs STAT3 activity, and combined use with Stattic further decreases breast cancer cell survival in vitro.

## Abstract

Aggressiveness and resistance to treatments are significant problems in cancer management. In this scenario, searching for new pharmacological targets for therapies is essential. The APE1 redox domain coactivates transcription factors that favor cancer malignancy. One of APE1's targets, STAT3, coordinates the transcription of genes involved in cancer hallmarks. However, the association between APE1 and STAT3 in the context of breast cancer cell survival and aggressiveness has not been previously characterized. Therefore, we investigated the role of the redox function of APE1 and STAT3 inhibitors in cell viability, proliferation, migration, invasion, and cell death. In addition, we verified the association between APE1 and STAT3 in breast cancer patient samples from TCGA and their relationship with proliferation and metastasis. Our results suggest that combined treatment with APE1 and STAT3 inhibitors can further synergistically reduce cell viability, proliferation, migration, and invasion, compared to treatment with inhibitors alone. Moreover, the APE1 and STAT3 activity levels positively correlated with proliferation and metastasis gene signatures. Thus, we suggest the APE1 redox domain and STAT3 as promising targets for new therapy strategies against breast cancer.

In this study, we first reported that APX2009 impairs STAT3 transcriptional activity in breast cancer cells, leading, in combination with Stattic, to a further decrease in the survival and aggressiveness of breast cancer cells in vitro, compared to treatments alone. Moreover, APE1 and STAT3 signatures are positively correlated in breast cancer data from TCGA and are positively correlated with proliferation and metastasis signatures. Therefore, dual‐targeting APE1 redox activity and STAT3 could be a promising new therapeutic approach against breast cancer.