Overexpression of ErbB2/Her2/neu is implicated in the induction of many human cancers. Similarly, increased expression of the lysosomal proteases, cysteine cathepsins, is observed in several cancers and correlates with enhanced angiogenesis, invasion and metastasis. Our recent studies show that ErbB2 levels correlate positively with the cathepsin B and L levels in primary breast cancer and that ErbB2 regulates the expression of cysteine cathepsins B and L in several ErbB2-positive breast cancer cells, contributing to the development of a highly invasive phenotype. We have recently also identified the signaling network that is essential for mediating the ErbB2-induced cysteine cathepsin B and L expression and invasionin vitro.This network involvesERK2-MAPK, but not ERK1-MAPK, three additional serine-threonine kinases and two transcription factors, MZF1 and ETS1 (1).
With a pharmacological protein kinase inhibitor screen, using Lapatinib as positive control, we have identified five inhibitors putatively targeting this previously unidentified ErbB2 signaling network. Our data shows that the treatment of ErbB2-positive cancer cells with these inhibitors specifically reduce cysteine cathepsin activity, lysosomal secretion and mRNA expression and invasion in 3-dimensional Matrigel cultures. We postulate that small molecular weight compounds that specifically target ErbB2-induced cancer cell invasion by for example inhibiting the identified signaling network could serve useful as alternative or additional treatment in cases where conventional ErbB2-targeted therapy is failing.
1. Rafn, B., Friberg Nielsen, Andersen, S.H., Szyniarowski, P., Corcelle-Termeau, E., Valo, E., Fehrenbacher, N., Olsen, C.J., Daugaard, M., Egebjerg, C., Bøttzauw,T., Kohonen, P., Nylandsted, J., Hautaniemi,S., Moreira, J., Jäättelä, M. and Kallunki, T. (2012)ErbB2-driven breast cancer cell invasion depends on a complex signalling network activation myeloid zinc-finger-1-dependent cathepsin B expression.Mol. Cell.45, 764-776.