Abstract #4719: Nrf2 and drug resistance in breast cancer cells

Breast Cancer is the leading cause of cancer deaths in women. Excellent chemotherapeutic drugs including aromatase inhibitors are available to reduce or eliminate breast cancer. However, breast tumor cells often become resistant to drugs resulting in the loss of their effectiveness against breast cancer. NF-E2 Related Factor 2 (Nrf2) is a nuclear transcription factor that activates a battery of defensive genes. INrf2 constitutively suppresses Nrf2 activity in the absence of stress by functioning as an adapter protein for Cul3/Rbx1 mediated ubiquitination and degradation of Nrf2. When a cell encounters any form of stress Nrf2 dissociates from the INrf2/Cul3-RBX1 complex and translocates into the nucleus. This leads to coordinated induction of a battery of genes encoding drug detoxifying enzymes, antioxidants, multi-drug resistance proteins, ubiquitin enzymes, and proteasomes that protects cells and promote cell survival. We hypothesized that breast cancer cells especially during persistent treatment with drugs generate high amounts of ROS and electrophiles that signals Nrf2 activation leading to drug resistance. Indeed, letrozole resistant breast cancer LTLT cells derived from MCF-7 aromatase expressing cells (MCF-7ca) demonstrated greater than ten-fold higher levels of Nrf2, as compared to drug sensitive MCF7ca cells. Further studies revealed that removal of letrozole treatment led to time dependent decline in Nrf2 levels in drug-resistant LTLT cells. It took approximately 96 hours of removal of letrozole to bring down the Nrf2 to the level in drug-sensitive MCF-7ca cells. The treatment of drug-sensitive MCF-7ca cells with letrozole led to stabilization and nuclear accumulation of Nrf2. Interestingly, antioxidant-mediated activation of Nrf2 in MCF-7 cells led to significantly reduced apoptosis in response to exposure to anti-tumor drug etoposide. The results combined suggest that persistent exposure of drugs leads to Nrf2 activation and drug resistance in breast cancer cells. The drug-resistance is presumably due to Nrf2 activation of proteins that detoxify drugs and neutralize free radicals that cause cell damage and death.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4719.