Metastatic breast cancer is therapeutically challenging and accounts for up to 90% of patient deaths. Triple Negative Breast Cancer (TNBC) is the molecular subtype that exhibits the poorest prognosis due to the lack of targeted therapies and oestrogen receptor negativity. Laminin-511 (LM-511) is a trimeric basement membrane glycoprotein (αβϒ trimers) that is abundantly produced by metastatic breast cancer and contributes to TNBC progression. Its interaction with integrin receptors (α3β1, α6β4, α6β1) promotes tumour cell survival migration and invasion but the therapeutic potential of targeting these interactions in TNBC has yet to be translated into the clinic. Disintegrins are a family of soluble polypeptides derived from snake venom that bind specifically to and inhibit integrins. Lebein-1 is a potent disintegrin that selectively binds to β1-type integrins, including LM-511-binding α3β1 and α6β1 integrin receptors. This inhibitor has shown efficacy in pre-clinical models of melanoma and colorectal cancer but has never been evaluated in TNBC.
Here, we demonstrate for the first time that Lebein-1 potently inhibits TNBC growth and vascularisation in vivo. We show that Lebein-1 induces apoptosis and significantly alters the morphology and phenotype of TNBC cells at low nanomolar concentrations in vitro. These changes are associated with alterations in transcriptional regulators and adhesion proteins that mediate mesenchymal to epithelial transition and mimic the effect of LM-511 suppression. Lastly, we present preliminary data on the design and functional characterisation of Lebein-1 synthetic peptides in view of clinical translation.
Collectively, these observations raise the exciting possibility that disruption of LM-511-integrin interactions could provide a new therapeutic approach for metastatic TNBC and warrant further investigation of Lebein-1 peptides in pre-clinical models.