Identification of microRNAs targeting the DNA damage response in breast cancer

Several in vivoand in vitro data demonstrated that the DNA damage response (DDR) plays a crucial role in tumorigenesisacting as an anti-cancer barrier. Indeed, cells respond to DNA breaks caused by both exogenous (e.g. chemicals, chemotherapeutics) and endogenous (e.g. deregulated function of oncogenes) sources of DNA damages by properly triggering the activation of the DDR. The latter involves the recruitment of DNA repair proteins to sites of damage and the activation of checkpoint mechanisms to slow down cell cycle progression, thus allowing DNA damage repair or, if the damage could not be repaired, leading to apoptosis or cellular senescence. As a consequence, alterations of DDR functionality have a deep impact on cell proliferation, survival, genomic instability and tumorprogression. microRNAs(miRNAs) are small non coding RNAs that finely regulate gene expression by binding the 3’UTR of their target mRNAs, thus altering theirtranslation, stability and localization. It has been shown that several miRNAsmodulate critical cellular processes deregulated in cancer, acting either as oncogenesor tumorsuppressors. In the present study, we focused on the identification of miRNAsas new modulators of DNA damage activated signalingin several normal and transformed breast cancer cells. In particular, we discovered that miR-181 family acts as a modulator of the levels of ATM (ataxia telangiectasiamutated) kinase, one of the most important proteins involved in sensing DNA double strand breaks and activating DDR. The role of miR-181 family in the DDR pathway, its involvement in the induction of cellular senescence triggered by oncogenicstress (OIS) and its relevance in breast cancer will be presented.