A MOLECULAR network that helps drive the spread of triple-negative breast cancer (TNBC) could provide a new target for treatment, new research shows.
According to a study published in EMBO Molecular Medicine, researchers identified low levels of the microRNA miR-342 as a marker of increased metastatic potential in TNBC. Restoring miR-342, or targeting its downstream pathway using the CDK4/6 inhibitor palbociclib, suppressed metastatic outgrowth in preclinical models.
Analysis of human breast cancer datasets also showed that patients with TNBC whose tumours had lower miR-342 levels had poorer overall survival. Researchers subsequently demonstrated in laboratory and mouse models that restoring miR-342 could suppress metastatic growth, and identified a way of targeting the same process using palbociclib, an existing breast cancer drug.
TNBC lacks expression of oestrogen receptor, progesterone receptor, and HER2. As a result, treatment options remain limited, particularly once the disease has metastasised, while the molecular heterogeneity of TNBC has complicated the development of effective targeted therapies.
Researchers investigated microRNAs, small molecules that help regulate gene expression within cells, to identify those associated with TNBC metastasis.
Their analysis highlighted miR-342. In both the METABRIC and Cancer Genome Atlas human breast cancer datasets, lower miR-342 levels were significantly associated with poorer overall survival in patients with TNBC, but not those with oestrogen receptor-positive breast cancer.
Restoring miR-342 in mouse models and models using human TNBC cells significantly reduced metastasis. Further experiments showed that its strongest effect occurred during the later stages of the metastatic process, limiting the growth of tumour cells after they had reached distant sites.
Molecular analysis revealed that miR-342 regulates multiple genes that converge on E2F signalling, a pathway involved in cell growth and division. Analysis of matched primary and metastatic TNBC patient-derived xenografts also showed increased E2F pathway activity in metastatic tumour cells alongside reduced expression of EVL, the host gene for miR-342.
The team tested whether E2F signalling could be indirectly targeted with palbociclib, a CDK4/6 inhibitor already used to treat some hormone receptor-positive breast cancers.
In a mouse model of TNBC, palbociclib treatment was started after cancer cells had already reached and colonised the lungs. Treatment significantly reduced their subsequent metastatic growth, suggesting that CDK4/6 inhibition could potentially help prevent disseminated cancer cells from developing into larger metastatic tumours.
The findings identify a potential subgroup of TNBC characterised by low miR-342 and high E2F activity that may be particularly responsive to CDK4/6 inhibition.
However, palbociclib was not tested in patients with TNBC in this study. Further research will therefore be required to determine whether the findings can be translated into an effective treatment strategy for patients. Nevertheless, the results highlight a potential new therapeutic avenue for a subgroup of TNBC with limited targeted treatment options.
Reference: Arnet VK et al. Metastasis of triple negative breast cancer is regulated by a targetable miR-342-E2F network. EMBO Mol Med. 2026. doi:10.1038/s44321-026-00496-4
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