Abstract

Chemotherapy still represents the most common and sometimes the only possible therapeutic option for advanced breast cancer. Its efficacy is profoundly threatened by intrinsic or acquired chemoresistance, which, in some cases, can be unexpectedly promoted by the chemotherapeutic drugs used. ETV7, a poorly characterized ETS factor with no established roles in breast cancer so far, is reported here to be activated at the transcriptional level by chemotherapy and be able to promote breast cancer cells chemoresistance. This project proposes a novel drug resistance circuitry in breast cancer cells, specifically to Doxorubicin, governed by the ETV7 repressive action on DNAJC15, a gene whose low expression was previously associated with drug resistance in breast and ovarian cancer. Moreover, the impact of ETV7 in causing drug resistance is proved here to extend also to another type of drug, 5-Fluorouracil (5-FU), a chemotherapeutic agent commonly used in combination with Doxorubicin for breast cancer treatment. In this case, additional novel ETV7 targets (DPYD and DPEP1) were established and can represent important mediators for ETV7-mediated resistance to 5-FU. Additional relevant data, relative to biological implications for ETV7 in breast cancer progression, is provided here by the ETV7 ChIP-seq analysis, which reveals the first reported in vivo mapping of ETV7 occupancy. Through ChIP-seq novel ETV7 direct targets have been identified, some of them yet unexplored in breast cancer; notably, their expression revealed to be capable of predicting breast cancer patients outcome. Furthermore, a possible control exerted by ETV7 on the TGF-β pathway, discovered by enrichment analysis on ChIP-seq ETV7 targets, suggests a different and opposing role for ETV7 activation in either advanced stage cancers or normal and early stage breast cancers. Taken collectively, the results from this project propose an important key role for ETV7 in triggering breast cancer multi-drug resistance phenotype in response to chemotherapy, by controlling the expression of specific targets.