Indole-3-carbinol and its N-alkoxy derivatives preferentially target ERα-positive breast cancer cells

Abstract

lndole-3-carbinol (l3C) is a natural anti-carcinogemc compound found at high concentrations in Brassica vegetables. I3C was recently reported to inhibit neutrophil elastase (NE) activity, while consequently limiting the proteolytic processing of full length cylin E into pro-tumorigenic low molecular weight cyclin E (LMW-E). In this study, we hypothesized that inhibition of NE activity and resultant LMW-E generation is critical to the anti-tumor effects of 13C. LMW-E was predominately expressed by ERα-negative breast cancer cell lines. However, ER α-positive cell lines demonstrated the greatest sensitivity to the anti-tumor effects of 13C, its more potent N-alkoxy denvatwes, We found that l3C was incapable of inhibiting NE ac:tivity or the generation of LMW-E. Therefore, this pathway did not: contribute to theanti-tumor activity of I3C, Gene expression analyzes idenufied ligand-activated aryl hydrocarbon receptor (AhR), which mediated sensitivity to the anti-tumor effects of 13C in ERa-positive MCF- cells. In this model system, the reactive oxygen species (ROS)-induced upregulation of ATE-, pro-apoptotic BH3-only proteins (e.g. NOXA) contributed to the sensitivity of ERa-positive breast cancer cells to the anti-tumor effects of l3C. Overexpression of ERα in MDA-MB -23 cells, which normally lack ERa expression, increased sensitivity to the anti-tumor elfects of l3C, demonstrating a drect role for ERa in mediating the sensitivity of breast cancer cell lines to BC. Our results suggest that ERa signaling amplified the pro -apoptotic effect of 13-C -signaling AhR signaling in luminal breast cancer cell lines, which was mediated in part through oxidative stress induced upregulation of ATF-3 and downstream BH3 -only proteins.