Proteomics of Patient-derived Breast Tumours Identifies a Pro-migratory Osteomodulin-Cyclin Dependent Kinase 1 Axis which Drives Bone Metastasis

Abstract

AbstractBreast cancer remains a leading cause of mortality, predominantly due to the development of metastases to vital organs. At present, predictive biomarkers of organ specific metastasis and therapies targeted to the metastatic niche are limited. Here, to identify the molecular determinants of breast cancer metastasis we analysed patient-derived breast tumours by combining quantitative proteomics, bioinformatics, and functional assaysin vitroandin vivo.We identified elevated levels of the protein Osteomodulin (OMD) associated with breast cancer bone metastases in patient-derived samples. OMD overexpression in the breast cancer MDA-MB-231 cell model significantly increases cell migrationin vitroand promotes the formation of bone metastasesin vivo. Phosphoproteomics analysis of MDA-MB-231 cells expressing OMD identifies active Cyclin-dependent kinase 1 (CDK1) downstream of OMD. The importance of the OMD-CDK1 axis was validated using two independent phosphoproteomics datasets analysing patient-derived breast cancer samples. We also show that the OMD-CDK1 axis drives cell migration and cell viabilityin vitroand the formation of bone metastasesin vivo. Finally, CDK1 inhibition reducesin vitrocell viability of an independent cohort of metastatic patient samples showing high CDK1 activity. Therefore, the OMD-CDK1 axis will determine which breast cancer patients develop bone metastases and is a therapeutic target to treat or prevent breast cancer bone metastases.