Rationale Approximately 2500 breast cancer patients die in Australia every year due to metastatic breast cancer disease.Metastasis is a multistep process where primary tumour cells escape and colonise distant organs. Of the multiple steps that have been hypothesized to lead to the acquisition of the lethal phenotype, the ability to survive underlies every stage to tissue wide dissemination. MCL-1 is a member of the BCL-2 family of pro-survival proteins, which regulate survival in a wide range of normal and malignant tissue types and may play a role the progression to metastatic disease.
Objective To investigate the role of MCL-1 in breast cancer cell survival and metastasis.
Methods and results We have created stable inducible triple negative breast cancer (TNBC) cell lines with a specific MCL-1 antagonist, BIMs2A, which inhibits MCL-1 activity and protein binding. Forced expression of the MCL-1 antagonist BIMs2A in MDA-MB-468 TNBC cells increased cell death and sensitised to cytotoxic therapy. Sensitivity was partially dependent on expression of BCL-2 or BCL-XL. MCL-1 antagonism in MDA-MB-231 TBNC cells reduced the invasiveness of MDA-MB-231 cells into a 3D organotypic matrix. In a refined intraductal xenograft model we have demonstrated that MCL-1 antagonism increased the latency to ethical endpoint in MDA-MB-468 TBNC xenografts and days to detection in MDA-MB-231 TBNC xenografts. In both MDA-MB-468 and MDA-MB-231 TNBC xenografts MCL-1 antagonism inhibited metastatic colonisation to the lung.
Conclusion Our data suggests that MCL-1 has the potential to be a key regulator of breast cancer metastasis and that targeting MCL-1 or its downstream effectors may provide new therapeutic options for the treatment of advanced breast disease.