Research from Hyo Jin Kang and Yong Weon Yi,etc. shows that HER2 confers drug resistance of human breast cancer cells through activation of NRF2 by direct interaction.

Taken together, the results of their research suggest that active HER2 (HER2CA) binds to NRF2 to activate the transcription of a set of genes which are involved in drug resistance of cancer cells at multiple levels. Various studies have demonstrated that HER2 or NRF2, independently, gives resistance of cancer cells to a range of therapeutics. However, no direct link, between HER2 and NRF2 in drug resistance of cancer cells, has ever been reported. In the present study, they first demonstrated the direct link between HER2 and NRF2 in drug resistance of cancer cells. Their present study suggests that HER2 may regulate NRF2 stability and/or activity through direct physical interaction. This HER2-NRF2 interaction may contribute to 1) stabilization of NRF2 by inhibiting or competing with KEAP1 similar to other proteins as previously reported. Data presented in this study support this possibility: 1) the expression of FLAG-NRF2 protein was increased in HER2CA-transfected MCF7 and HEK293T cells and a GFP-tag, which inhibits polyubiquitination-dependent proteasomal degradation, increased NRF2 protein expression in HEK293T cells even in the absence of HER2CA expression; 2) enhancing translocation of NRF2 into nucleus; or 3) recruitment of HER2, as a coactivator, to the promoters of NRF2-target genes. In fact, it has been reported that HER2 is localized in the nucleus of cells to act as a transcriptional activator. Further studies are needed to determine the exact roles of HER2-NRF2 interaction in regulation of drug resistance in HER2-amplified or -activated human cancer cells.

Reference

HER2 confers drug resistance of human breast cancer cells through activation of NRF2 by direct interaction, Scientific Reports 4, Article number: 7201︱doi:10.1038/srep07201