Background: Metastatic disease is largely resistant to therapy and accounts for
almost all cancer deaths. Myeloid cell leukemia-1 (MCL-1) is an important regulator
of cell survival and chemo-resistance in a wide range of malignancies, and thus its
inhibition may prove to be therapeutically useful.
Methods: To examine whether targeting MCL-1 may provide an effective treatment
for breast cancer, we constructed inducible models of BIMs2A expression (a specific
MCL-1 inhibitor) in MDA-MB-468 (MDA-MB-468-2A) and MDA-MB-231 (MDAMB-
231-2A) cells.
Results: MCL-1 inhibition caused apoptosis of basal-like MDA-MB-468-2A cells
grown as monolayers, and sensitized them to the BCL-2/BCL-XL inhibitor ABT-263,
demonstrating that MCL-1 regulated cell survival. In MDA-MB-231-2A cells, grown
in an organotypic model, induction of BIMs2A produced an almost complete
suppression of invasion. Apoptosis was induced in such a small proportion of these
cells that it could not account for the large decrease in invasion, suggesting that MCL-
1 was operating via a previously undetected mechanism. MCL-1 antagonism also
suppressed local invasion and distant metastasis to lung in mouse mammary
intraductal xenografts. Kinomic profiling revealed that MCL-1 antagonism modulated
Src family kinase targets, which suggested that MCL-1 might act as an upstream
modulator of invasion via this pathway. Inhibition of MCL-1 in combination with
dasatinib suppressed invasion in 3D models of invasion and inhibited the
establishment of tumors in vivo.
Conclusion: These data provide the first evidence that MCL-1 drives breast cancer
cell invasion and suggests that MCL-1 antagonists could be used alone or in
combination with drugs targeting Src kinases such as dasatinib to suppress metastasis.