Avoidance of apoptosis is a hallmark of cancer; hence there is a great interest in developing therapies that reactivate cell death. The pro-survival protein MCL-1 is over-expressed in cancer and confers resistance to therapy, however the mechanism by which MCL-1 regulates cell survival is not fully understood.
We aim to investigate the mechanisms underlying MCL-1 dependent survival and chemo-resistance in breast cancer and determine if MCL-1 antagonism, using a specific MCL-1 ligand, BIMs2A, primes cancer cells for death.
Forced expression of the MCL-1 antagonist BIMs2A in MDA-MB-468 triple negative breast cancer (TNBC) cells resulted in increased cell death and cytotoxic sensitivity to ABT-737 and irradiation. Sensitivity was partially dependent on expression of BCL-2 or BCL-XL. Furthermore we observed that forced expression of BIMs2A in TNBC cells, increased β1-integrin expression and repartitioned one of its downstream kinases, FAK, to the heavy membrane. β1-integrin and FAK are key components of adhesion signalling in breast epithelial cells. Loss of detachment triggers integrin/FAK signalling and leads to localisation of BAX to the mitochondria resulting in anoikis. We show that MCL-1 antagonism by BIMs2A results in increased anoikis of MDA-MB-468 cell lines when grown on PolyHEMA. We also detected a novel protein-protein interaction of MCL-1 with the 110kDa isoform of β1-integrin in TNBC cell lines.
These data demonstrate that MCL-1 regulates cytotoxic resistance and survival during anoikis of MCL-1 expressing TNBC cell lines, via canonical survival pathways and an interaction with the β1-integrin/FAK adhesion signalling cascade. Thus targeting MCL-1 activity may provide a novel therapeutic target to prevent the dissemination of breast tumour cells during metastasis.