MCL-1 regulates breast cancer stem cells.


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Kirsteen Campbell1,Karen Blyth2,Stephen Tait3
1Glasgow University/ CRUK Beatson Institute,2CRUK Beatson Institute,3Glasgow University/CRUK Beatson Institute

Abstract

Background

MCL-1 is a pro-survival member of the BCL-2 protein family that has been shown to be up-regulated in a range of cancers. We have shown that high levels of MCL-1 predict poor prognosis in breast cancer. This is particularly relevant in triple negative breast cancer where treatment resistance and disease recurrence remain a major challenge. A new class of drugs specifically targeting MCL-1 have been developed and are currently in clinical trials for haematopoietic malignancies. We are investigating the therapeutic potential of targeting MCL-1 in breast cancer and the role of MCL-1 in breast cancer stem cells.

 

Method

We have used a combination of approaches to systematically evaluate the role of MCL-1 in breast cancer. This includes the use of small molecule MCL-1 inhibitors and knock-down/knock-out of MCL-1 in vitro and in vivo xenograft/genetically engineered mouse models to investigate the therapeutic potential of targeting MCL-1 in breast cancer.

Results

We find that in addition to the poor prognosis indicated by high levels of MCL-1, breast cancer cells are highly dependent on MCL-1. Therapeutic targeting or genetic deletion of MCL-1 is sufficient to delay tumour development and regress established tumours in vivo. We find that MCL-1 is important in breast cancer stem cells and targeting MCL-1 could be particularly important in the context of treatment resistance and recurrence.

Conclusion

New targeted therapeutic approaches are required in both triple negative breast cancer and treatment resistant/recurrent disease. Our evidence suggests that targeting MCL-1 may offer a new therapeutic axis in breast cancer.