Abstract

ETV7 is a poorly characterized transcriptional repressor that belongs to the large family of ETS transcription factors, whose members have been associated with several cancer-related processes. ETV7 is a well-recognized Interferon-stimulated gene (ISG), and it was shown that its expression can be synergistically induced by the combined treatment with the chemotherapeutic drug Doxorubicin and the inflammatory cytokine TNFa in different cancer cell lines, including the breast cancer-derived MCF7 cells. Recently, it has been shown that ETV7 expression is significantly increased in breast cancer tissues, compared to the normal breast; however, the roles and the impact of ETV7 expression in breast cancer have still to be elucidated. This project aimed at understanding the effects caused by increased ETV7 expression on breast cancer (BC) progression and resistance to conventional anti-cancer drugs. We first observed that ETV7 expression can be induced by different stimuli, particularly by the treatment with several chemotherapeutic drugs able to induce DNA damage. We also demonstrated that the expression of ETV7 could affect the sensitivity of BC cell lines to standard anti-cancer therapies, such as Doxorubicin, 5-Fluorouracil and radiotherapy, and this evidence was correlated with an increase in ABC transporters and anti-apoptotic proteins expression. By investigating the possible mechanism responsible for ETV7-dependent Doxorubicin resistance we identified a novel target gene of ETV7, DNAJC15, which is a co-chaperone protein whose repression was previously associated with drug resistance. Given the ability of cancer stem cells (CSCs) to be more chemoresistant, we analyzed the effects of ETV7 expression on the sub-population of breast CSCs. We found that ETV7 expression could exert a strong effect on breast cancer cells stemness, confirmed by both an increase in CD44+/CD24low population and mammosphere formation efficiency. In order to investigate the mechanisms responsible for these effects, we performed an RNA-seq analysis, which revealed significant repression of a signature of Interferon-stimulated genes, suggesting a possible negative feedback mechanism in the regulation of the response to Interferon. Finally, prolonged treatment of breast cancer cells with IFNb was able to rescue the effects on CSCs content. Taken collectively, our data revealed that ETV7 can affect the sensitivity of breast cancer cells to some chemotherapeutic drugs and we propose ETV7 as an important contributor to the tumor-initiating capabilities of BC cells.