Protective role of miR-155 in breast cancer through RAD51 targeting impairs homologous recombination after irradiation.

Abstract

Cell survival after DNA damage relies on DNA repair, the abrogation of which causes genomic instability and development of cancer. However, defective DNA repair in cancer cells can be exploited for cancer therapy using DNA-damaging agents. DNA double-strand breaks are the major lethal lesions induced by ionizing radiation (IR) and can be efficiently repaired by DNA homologous recombination, a system that requires numerous factors including the recombinase RAD51 (RAD51). Therapies combined with adjuvant radiotherapy have been demonstrated to improve the survival of triple-negative breast cancer patients; however, such therapy is challenged by the emergence of resistance in tumor cells. It is, therefore, essential to develop novel therapeutic strategies to overcome radioresistance and improve radiosensitivity. In this study we show that overexpression of microRNA 155 (miR-155) in human breast cancer cells reduces the levels of RAD51 and affects the cellular response to IR. miR-155 directly targets the 3'-untranslated region of RAD51. Overexpression of miR-155 decreased the efficiency of homologous recombination repair and enhanced sensitivity to IR in vitro and in vivo. High miR-155 levels were associated with lower RAD51 expression and with better overall survival of patients in a large series of triple-negative breast cancers. Taken together, our findings indicate that miR-155 regulates DNA repair activity and sensitivity to IR by repressing RAD51 in breast cancer. Testing for expression levels of miR-155 may be useful in the identification of breast cancer patients who will benefit from an IR-based therapeutic approach.

• Authors: Pierluigi Gasparini, Francesca Lovat, Matteo Fassan, Lucia Casadei, Luciano Cascione, Naduparambil K Jacob, Stefania Carasi, Dario Palmieri, Stefan Costinean, Charles L Shapiro, Kay Huebner, Carlo M Croce
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 111 Issue 12 Pg. 4536-41 (Mar 25 2014) ISSN: 1091-6490 [Electronic] United States
• PMID: 24616504 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• MIRN155 microRNA, human
• MicroRNAs
• RAD51 protein, human
• Rad51 Recombinase

Topics

• Breast Neoplasms (genetics, prevention & control, radiotherapy)
• Female
• Homologous Recombination (radiation effects)
• Humans
• MCF-7 Cells
• MicroRNAs (physiology)
• Models, Biological
• Prognosis
• Rad51 Recombinase (genetics)
• Radiation Tolerance