Taxane resistance in breast cancer: a closed HER2 circuit?

Abstract

Microtubule inhibitors, such as the taxanes docetaxel and paclitaxel, are commonly used drugs for the treatment of breast cancer. Although highly active in a large fraction of individuals a considerable number of patients show poor response due to either intrinsic or acquired drug resistance. Extensive research in the past identified several taxane resistance-related mechanisms being activated by pathologically altered single gene function. To date, however, a clinically relevant predictive biomarker for taxanes has not been derived yet from this knowledge, most likely due to the manifold of resistance mechanisms that may combine in one tumor, thereby fostering escape from taxane cytotoxicity. Here, we aimed to comprehensively review the current literature on taxane resistance mechanisms in breast cancer. Interestingly, besides altered microtubule physiology we identified the HER2 signaling cascade as a major dominator influencing several routes of cytotoxicity escape, such as cell survival, apoptosis, drug efflux, and drug metabolism. Furthermore, the transcription factor YBX-1, activated by HER2, facilitates a sustaining HER2 signaling feedback loop contributing to the establishment of cellular survival detours. In conclusion, taxane resistance in breast cancer follows a multiplex establishment of drug cytotoxicity escape routes, which may be most efficiently therapeutically targeted by interference with their mutually governing signaling nodes.