Metastasis of triple negative breast cancer is regulated by a targetable miR-342-E2F network

Abstract

Triple-negative breast cancer (TNBC) has a high incidence of metastasis and limited therapeutic options. Here, we identify a multimodal and targetable miR-342-E2F network that regulates metastatic outgrowth in TNBC. Through integrating clinical and experimental datasets, we uncover miR-342 as a suppressor of TNBC metastasis. Temporal re-expression of miR-342 significantly inhibited metastatic progression in both immunocompetent and xenograft TNBC models by specifically limiting the outgrowth of disseminated tumour cells. Using multi-omics profiling, we identified the global complement of miR-342 targets, demonstrating that it directly suppresses transcriptional and post-transcriptional networks that converge to dampen E2F signalling. Single-cell analysis of matched primary and metastatic patient-derived TNBC samples reveals activation of E2F signalling in metastasis that corresponds with reduced miR-342 host gene EVL expression. Furthermore, pharmacologic inhibition of this pathway with the CDK4/6 inhibitor palbociclib specifically reduces metastatic outgrowth of pre-established TNBC lesions. Our findings reveal that TNBCs with low miR-342/high E2F signalling have increased metastatic competency and may be amenable to CDK4/6 inhibitor therapy, offering a potential strategy for targeted intervention to limit TNBC metastasis. Triple negative breast cancers (TNBC) exhibit high rates of metastasis and have few treatment options. As TNBC are heterogeneous, subgroups may be vulnerable to specific treatments. We identify a miR-342-E2F network that regulates metastatic outgrowth of TNBC and is targetable by CDK4/6 inhibition. MiR-342 limits the metastatic outgrowth of disseminated TNBC cells. MiR-342 directly suppresses transcriptional and post-transcriptional networks that cooperatively dampen E2F signaling. TNBCs with reduced miR-342 and elevated E2F signaling are associated with poor outcomes. Pharmacological inhibition of E2F signaling using the CDK4/6 inhibitor palbociclib reduces metastatic outgrowth in a TNBC mouse model. MiR-342 limits the metastatic outgrowth of disseminated TNBC cells. MiR-342 directly suppresses transcriptional and post-transcriptional networks that cooperatively dampen E2F signaling. TNBCs with reduced miR-342 and elevated E2F signaling are associated with poor outcomes. Pharmacological inhibition of E2F signaling using the CDK4/6 inhibitor palbociclib reduces metastatic outgrowth in a TNBC mouse model. Triple negative breast cancers (TNBC) exhibit high rates of metastasis and have few treatment options. As TNBC are heterogeneous, subgroups may be vulnerable to specific treatments. We identify a miR-342-E2F network that regulates metastatic outgrowth of TNBC and is targetable by CDK4/6 inhibition.