Abstract LB-198: Ryl hydrocarbon receptor agonist Aminoflavone disrupts mammosphere formation via alpha 6 integrin inhibition

Abstract

Abstract Introduction: Emerging evidence has suggested that cancer stem cells (CSCs) play a prominent role in the initiation and dissemination of a myriad of malignancies including breast cancer. CSCs have the capacity to self-renew within heterogeneous tumor cells. Currently available therapeutic options for breast cancer are incapable of suppressing CSC growth. Alpha 6 integrin contributes to CSC growth while aryl hydrocarbon receptor (AhR) activation impedes CSC proliferation. AhR agonist Aminoflavone, a synthetic flavonoid, is currently undergoing clinical evaluation for the treatment of breast cancer. We hypothesize that Aminoflavone alters the integrity and formation of cell suspension clusters initiated by breast cancer stem cells (mammospheres) by modulating alpha 6 integrin expression in an AhR-dependent manner Experimental Procedures: Mammospheres derived from MCF-7 breast cancer cells were exposed to Aminoflavone at varying times. We also treated mammospheres with Tamoxifen an anticancer agent frequently used in the treatment of breast cancer. Following Aminoflavone treatment, cells were analyzed microscopically to evaluate alterations in mammosphere structure. In addition, the expression of molecular targets associated with CSC growth in addition to alpha 6 integrin were evaluated by Western blotting and quantitative RT-PCR analysis. Results: We observed that Aminoflavone, but not Tamoxifen, disaggregates MCF-7 mammospheres. In contrast, Aminoflavone did not affect mammospheres produced from AhR defective MCF-7 (AHR100) cells. Aminoflavone abrogated the ability of secondary mammospheres to form. In addition, alpha-6-integrin expression was abolished following Aminoflavone treatment in MCF-7 but not AHR100 cells. The expression of several genes whose products regulate alpha-6 integrin expression were also modulated following Aminoflavone treatment in MCF-7 cells. Conclusion: These data suggest that Aminoflavone disrupts mammosphere formation via AhR signaling activation that results in alpha 6 integrin inhibition. These findings support continued efforts to develop novel AhR ligands with efficacy against breast CSCs as a viable therapeutic strategy for breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-198. doi:1538-7445.AM2012-LB-198