HER-2 and NF-kappaB as the targets for therapy-resistant breast cancer

Abstract

HER-2 (also called ErbB2 or Neu) tyrosine kinase, one of the four members of ErbB receptor family (ErbB1, i.e., EGFR ErbB2, ErbB3 and ErbB4), plays a critical role in the control of diverse cellular functions involved in differentiation, proliferation, migration and cell survival via multiple signal transduction pathways. Overexpression of HER-2, observed in HER-2-positive breast cancer patients, is believed to cause the tumor resistance to an array of anti-cancer agents and poor prognosis. Although HER-2 antibodies have shown growth inhibitory effects, more efficient molecular targets against HER-2-mediated tumor resistance need to be developed. The molecular mechanisms underlying HER-2-mediated tumor resistance, especially the connections between HER-2 and therapy-resistant signaling networks, need to be further investigated. NF-kappaB, a key stress transcription factor that can initiate a pro-survival network, was found to be activated in many cancer cells overexpressing HER-2 and to be responsible for the radiation resistance in HER-2 transfected breast cancer cells. Recent findings in literature and data from this laboratory suggest a possible co-operation between HER-2 and NF-KB in signaling tumor resistance to radiotherapy. This review will discuss the mechanisms of HER-2 mediated NF-kappaB signaling pathway and potential target for therapeutic intervention.

Figure 1

Signaling network of HER-2-mediated NF-κB activation in radio- andlor chemo-resistant breast cancer cells. overexpression of HER-2 firstly activates pI3K/Akt pathway that, in turn, activates NF-κB. Activated NF-κB then induces a group of pro-survival genes including cyclin B1, mitochondrial antioxidant MnSOD and importantly, the HER-2 gene itself, leading to the radio-and/or chemo-resistant phenotype in HER-2-positive cancer cells.