MiR-342 suppression of an E2F signaling network limits metastatic outgrowth of triple negative breast cancer [RNA-Seq]

Metastasis occurs with high frequency in patients with triple negative breast cancer (TNBC) and its aetiology remains poorly understood. Through integrated analysis of metastatic TNBC mouse models and patient datasets, we identified miR-342 as a clinically relevant suppressor of TNBC metastasis. Ectopic expression of miR-342 was sufficient to repress TNBC metastasis in immune competent and xenograft mouse models, specifically limiting the outgrowth of disseminated tumour cells. Using a multi-omics approach, including Argonaute-HITS-CLIP, we identified the global complement of miR-342 targets in TNBC. Through targeting of E2F1 and many downstream E2F target genes, miR-342 orchestrates both transcriptional and post-transcriptional regulatory networks that converge to suppress E2F signalling in TNBC. Consistent with this, inhibition of the E2F pathway with the CDK4/6 inhibitor palbociclib reduces metastatic outgrowth of TNBC. These findings demonstrate the existence of a pro-metastatic E2F pathway that is downregulated by miR-342 and implicate the clinical utility of CDK4/6 inhibitors to limit TNBC metastasis in patients where the tumour expresses low levels of miR-342.