Pro-survival BCL-2 family protein MCL-1 is one of the most frequently amplified genes in breast cancer, particularly in ‘basal-like’ triple-negative breast cancer (TNBC). The outcome of most patients diagnosed with TNBC is especially poor, as post-surgical disease recurrence and mortality occurs in 50-80% of cases. The dismal prognosis of TNBC patients is caused by (1) increased propensity for metastasis; (2) high rates of post-treatment relapse and/or therapeutic resistance; (3) a paucity of targeted treatment options.
We have previously demonstrated that MCL-1 protein expression in a large breast cancer tissue microarray cohort was predictive of poor outcome in treatment naive TNBC, thus representing an attractive therapeutic opportunity.
We demonstrate that targeting MCL-1 restricts mammary tumour formation and promotes regression of established tumours in vivo. This is due to the canonical function of MCL-1 in the intrinsic apoptotic pathway where we uncover a requirement for MCL-1 in breast cancer stemness, and in silico analysis of breast cancer datasets highlights the correlative relationship between MCL-1 expression and markers of cancer stem-like cell behaviour. Targeted inhibitors of MCL-1 are currently undergoing clinical trials for the treatment of haematological malignancies, and our evidence suggests that targeting MCL-1 may offer a valuable new therapeutic option in TNBC patients.