No abstract

Significance Cell survival after DNA damage relies on DNA repair, the abrogation of which causes genomic instability and development of cancer. DNA double-strand breaks are lesions induced by ionizing radiation (IR) and can be efficiently repaired by DNA homologous recombination, a system that requires RAD51 recombinase (RAD51). Here we show that overexpression of miR-155 in human breast cancer cells reduces the levels of RAD51 and affects the cellular response to IR. 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. Testing triple-negative breast cancer patients for miR-155 expression may be a useful prognostic tool to identify who will benefit from an IR-based therapeutic approach.

Despite the development of combined modality treatments against liposarcoma (LPS) in recent years, a significant proportion of patients respond only modestly to such approaches, possibly contributing to local or distant recurrence. Early detection of recurrent or metastatic disease could improve patient prognosis by triggering earlier clinical intervention. However, useful biomarkers for such purposes are lacking. Using both patient plasma samples and cell lines, we demonstrate here that miR-25–3p and miR-92a-3p are secreted by LPS cells through extracellular vesicles and may be useful as potential biomarkers of disease. Both miR-25–3p and miR-92a-3p stimulated secretion of pro-inflammatory cytokine IL-6 from tumor-associated macrophages (TAM) in a TLR7/8-dependent manner, which in turn promoted LPS cell proliferation, invasion, and metastasis via this interaction with the surrounding microenvironment. Our findings provide novel and previously unreported insight into LPS progression, identifying communication between LPS cells and their microenvironment as a process critically involved in LPS progression. This study establishes the possibility that the pattern of circulating miRNAs may identify recurrence prior to radiological detectability while providing insight into disease outcome and as a possible approach to monitor treatment efficacy. Precis: Two extracellular vesicle-derived microRNAs are found to drive liposarcoma progression by stimulating the secretion of pro-inflammatory IL-6 from tumor-associated macrophages, offering new theranostic opportunities in this cancer setting.