Cancer cells can survive treatment with anticancer drugs by becoming resistant to cell death — often by acquiring defects in components of the apoptotic pathway. Donald Kufe and colleagues now report in Cancer Cell that MUC1 overexpression, which occurs in most carcinomas, could be a new way by which cancer cells avoid death.

MUC1 is cleaved in the endoplasmic reticulum and forms a heterodimer comprising the amino and carboxyl termini that localizes to the cell surface. The C terminus can be phosphorylated at tyrosine-46 (Y46) by the epidermal growth factor receptor (EGFR), and this induces its binding to β-catenin, so forming a link between the EGFR and WNT signalling pathways. When transfected into MUC1-negative HCT116 colorectal cancer cells, the C terminus of wild-type MUC1 was found to localize to mitochondria, as well as the cell surface. However, the C terminus of a MUC1 Y46F mutant, that could not be phosphorylated, displayed significantly less mitchondrial localization. Heregulin — but not EGF — further stimulated the mitochondrial localization of the C terminus of wild-type MUC1.

So, what function might the C terminus of MUC1 have when bound to the mitochondrial membrane? One possibility is that it regulates the intrinsic apoptotic pathway, which operates through release of cytochrome c from mitochondria. When HCT116 cells are treated with DNA-damaging agents such as the chemotherapeutic agent cisplatin, about 40% undergo apoptosis within 24 hours. This is associated with various subcellular changes, including an increase in cytochrome c release and cleavage of pro-caspase 3. These changes are attenuated when wild-type MUC1, but not the MUC1 Y46F mutant, is expressed, and the cells do not undergo apoptosis. Interestingly, MUC1 also attenuates apoptosis induced by TRAIL, which acts through the extrinsic death receptor pathway.

The mitochondrial localization of the C terminus of MUC1 does not seem to be restricted to colorectal cancer cells — both lung and breast carcinoma cells that endogenously express MUC1 show this localization pattern. Downregulating MUC1 in these cells using RNA interference results in their sensitization to chemotherapeutic agents such as cisplatin and etoposide.

But does MUC1 also affect chemosensitivity in vivo? Cells that either did or did not express MUC1 were injected subcutaneously into nude mice, where they formed tumours. The mice were treated with cisplatin, but tumour growth was only inhibited in those that did not express MUC1.

So, MUC1 seems to affect the chemosensitivity of cells to anticancer drugs. Targeting MUC1 to increase the effectiveness of anticancer drugs could be an important strategy in those cancer types in which it is overexpressed.