Indole-3-carbinol and its N-alkoxy derivatives preferentially target ER?-positive breast cancer cells.

ABSTRACT: Indole-3-carbinol (I3C) is a natural anti-carcinogenic 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 cyclin 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 I3C. LMW-E was predominately expressed by ER?-negative breast cancer cell lines. However, ER?-positive cell lines demonstrated the greatest sensitivity to the anti-tumor effects of I3C and its more potent N-alkoxy derivatives. We found that I3C was incapable of inhibiting NE activity or the generation of LMW-E. Therefore, this pathway did not contribute to the anti-tumor activity of I3C. Gene expression analyzes identified ligand-activated aryl hydrocarbon receptor (AhR), which mediated sensitivity to the anti-tumor effects of I3C in ER?-positive MCF-7 cells. In this model system, the reactive oxygen species (ROS)-induced upregulation of ATF-3 and pro-apoptotic BH3-only proteins (e.g. NOXA) contributed to the sensitivity of ER?-positive breast cancer cells to the anti-tumor effects of I3C. Overexpression of ER? in MDA-MB-231 cells, which normally lack ER? expression, increased sensitivity to the anti-tumor effects of I3C, demonstrating a direct role for ER? in mediating the sensitivity of breast cancer cell lines to I3C. Our results suggest that ER? signaling amplified the pro-apoptotic effect of I3C-induced 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.

SUBMITTER: Caruso JA 

PROVIDER: S-EPMC4614451 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature