Induction of Aryl Hydrocarbon Receptor-Mediated Cancer Cell-Selective Apoptosis in Triple-Negative Breast Cancer
Daniel J Elson1, Bach D Nguyen1, Sebastian Bernales2,3
1Cancer Research Laboratory, Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, Oregon, 97331, United States.
Abstract:
Triple-negative breast cancer (TNBC) remains a disease with a paucity of targeted treatment opportunities. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that is involved in a wide range of physiological processes, including the sensing of xenobiotics, immune function, development, and differentiation. Different small-molecule AhR ligands drive strikingly varied cellular and organismal responses. In certain cancers, AhR activation by select small molecules induces cell cycle arrest or apoptosis via activation of tumor-suppressive transcriptional programs. AhR is expressed in triple-negative breast cancers, presenting a tractable therapeutic opportunity. Here, we identify a novel ligand of the aryl hydrocarbon receptor that potently and selectively induces cell death in triple-negative breast cancer cells and TNBC stem cells via the AhR. Importantly, we found that this compound, Analog 523, exhibits minimal cytotoxicity against multiple normal human primary cells. Analog 523 represents a high-affinity AhR ligand with potential for future clinical translation as an anticancer agent.
Insights
A novel aryl hydrocarbon receptor (AhR) ligand, Analog 523, effectively targets triple-negative breast cancer (TNBC) cells and TNBC stem cells. This compound shows minimal toxicity to normal cells, offering a promising new therapeutic avenue for TNBC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Triple-negative breast cancer (TNBC) lacks targeted therapies.
- The aryl hydrocarbon receptor (AhR) is a transcription factor implicated in various cellular processes.
- AhR activation can induce anti-cancer effects in some malignancies.
Purpose of the Study:
- To identify novel therapeutic agents for TNBC.
- To investigate the potential of AhR ligands as a treatment strategy for TNBC.
- To evaluate a novel AhR ligand, Analog 523, for its efficacy and selectivity against TNBC.
Main Methods:
- Identification and characterization of a novel AhR ligand.
- Assessment of the compound's cytotoxicity against TNBC cell lines and TNBC stem cells.
- Evaluation of the compound's selectivity by testing against normal human primary cells.
Main Results:
- A novel, high-affinity AhR ligand, Analog 523, was identified.
- Analog 523 potently and selectively induces cell death in TNBC cells and TNBC stem cells.
- Analog 523 demonstrated minimal cytotoxicity against normal human primary cells.
Conclusions:
- Analog 523 is a potent and selective AhR ligand with significant anti-TNBC activity.
- The compound targets both TNBC cells and TNBC stem cells.
- Analog 523 holds potential for clinical translation as a targeted therapy for triple-negative breast cancer.
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