Breast cancer dependence on MCL-1 is due to its canonical anti-apoptotic function-AAM

Kirsteen J Campbell, Susan M Mason, Matthew : Winder, Rosalie BE Willemsen, Catherine Cloix, Hannah Lawson, Nicholas Rooney, Sandeep Dhayade, Andrew H Sims, Karen Blyth, Stephen W.G. Tait

Research output: Contribution to journalArticlepeer-review

Abstract

High levels of the anti-apoptotic BCL-2 family member MCL-1 are frequently found in breast cancer and, appropriately, BH3-mimetic drugs that specifically target MCL-1’s function in apoptosis are in development as anti-cancer therapy. MCL-1 also has reported non-canonical roles that may be relevant in its tumour-promoting effect. Here we investigate the role of MCL-1 in clinically relevant breast cancer models and address whether the canonical role of MCL-1 in apoptosis, which can be targeted using BH3-mimetic drugs, is the major function for MCL-1 in breast cancer. We show that MCL-1 is essential in established tumours with genetic deletion inducing tumour regression and inhibition with the MCL-1 specific BH3-mimetic drug S63845 significantly impeding tumour growth. Importantly, we found that the anti-tumour functions achieved by MCL-1 deletion or inhibition were completely dependent on pro-apoptotic BAX/BAK. Interestingly, we find MCL-1 is also critical for stem cell activity in human breast cancer cells and high MCL1 expression correlates with
stemness markers in tumours. This strongly supports the idea that the key function of MCL-1 in breast cancer is through its anti-apoptotic function. This has important implications for the future use of MCL-1 specific BH3-mimetic drugs in breast cancer treatment.
Original languageEnglish
JournalCell Death and Differentiation
Early online date31 Mar 2021
DOIs
Publication statusE-pub ahead of print - 31 Mar 2021

Keywords

  • MCL-1
  • BH3-mimetic
  • breast cancer
  • apoptosis

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