Targeting TRIM37-driven centrosome dysfunction in 17q23-amplified breast cancer
CHAPMAN J., Yeow ZY., Lambrus B., Marlow R., Zhan K., Durin M-A., Evans L., Scott P., Phan T., Park E., Ruiz L., MORALLI D., Knight E., Badder L., Novo D., Haider S., GREEN C., Tutt A., Lord C., Holland A.
Genomic instability (GI) is a hallmark of cancer and plays a central role in breast cancer initiation and development1,2. The success of Poly-ADP ribose polymerase inhibitors in the treatment of homologous recombination (HR)-deficient breast cancers exemplifies the utility of synthetic lethal genetic interactions in the treatment of GI-driven breast cancer3. Given that HR-defects are present in only a subset of breast cancers, there is a need to identify additional GI-driver mechanisms, and targeted strategies to exploit these defects in cancer treatment. Here, we identify that centrosome-depletion induces synthetic lethality in cancer cells harbouring the 17q23 amplicon, a recurrent copy number aberration (CNA) that defines ~9% of all breast tumours and is associated with high GI4-6. Specifically, small-molecule inhibition of Polo-like kinase 4 (PLK4) leads to centrosome depletion that triggers mitotic catastrophe in cells harbouring amplicon-directed overexpression of TRIM37. To explain this effect, we identify TRIM37 as a negative regulator of centrosomal pericentriolar material (PCM). In 17q23-amplified cells, elevated TRIM37 blocks the formation of non-centrosomal PCM foci, structures with microtubule nucleating capacity that are required for successful cell division in the absence of centrosomes. Lastly, we find TRIM37 overexpression causes GI by delaying centrosome maturation and separation at mitotic entry and thereby increasing the frequency of mitotic errors. Collectively, these findings highlight TRIM37-dependent GI as a putative driver event in 17q23-amplified breast cancer and provide a rationale for centrosome-targeting therapeutics in their treatment.