Induction of Aryl Hydrocarbon Receptor-Mediated Cancer Cell-Selective Apoptosis in Triple-Negative Breast Cancer Cells by a High-Affinity Benzimidazoisoquinoline

Triple-negativebreast cancer (TNBC) remains a diseasewith a paucityof targeted treatment opportunities. The aryl hydrocarbon receptor(AhR) is a ligand-activated transcription factor that is involvedin a wide range of physiological processes, including the sensingof xenobiotics, immune function, development, and differentiation.Different small-molecule AhR ligands drive strikingly varied cellularand organismal responses. In certain cancers, AhR activation by selectsmall molecules induces cell cycle arrest or apoptosis via activationof tumor-suppressive transcriptional programs. AhR is expressed intriple-negative breast cancers, presenting a tractable therapeuticopportunity. Here, we identify a novel ligand of the aryl hydrocarbonreceptor that potently and selectively induces cell death in triple-negativebreast cancer cells and TNBC stem cells via the AhR. Importantly,we found that this compound, Analog 523, exhibits minimal cytotoxicityagainst multiple normal human primary cells. Analog 523 representsa high-affinity AhR ligand with potential for future clinical translationas an anticancer agent.