Abstract 1304: Aryl hydrocarbon receptor ligands 5F 203 and 3,3'-Diindolylmethane disrupt mammospheres derived from MCF-7 cells and induce tumor suppressor miR125b-2 expression

Abstract

Abstract While anti-estrogen tamoxifen (Tam) effectively treats many patients with estrogen receptor positive (ER+) tumors, up to 40% experience relapse following resistance. Breast cancer stem cells (CSCs) within tumors greatly contribute to tamoxifen resistance (TamR) and exhibit unique molecular signatures that drive metastasis and promote relapse. Tumor suppressor miRNAs aid in suppressing breast cancer progression. We have previously shown that aryl hydrocarbon receptor (AhR)-ligand Aminoflavone disrupts the formation of spheres and inhibits the expression of putative stemness marker α6-integrin and α6-integrin-src-Akt signaling. We hypothesize that two AhR ligands, 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F 203) and 3,3'-Diindolylmethane (DIM), exhibit anticancer properties in MCF-7 breast cancer cells by targeting the CSC population in an AhR-dependent fashion. We found that DIM and 5F 203 disrupted mammospheres derived from MCF-7 cells but demonstrated a reduced capacity to do so in mammospheres derived from AHR100 cells (MCF-7 variants that are AhR-unresponsive). Wound healing and colony forming assays respectively revealed that 5F 203 and DIM also decreased cell migration and cell proliferation in MCF-7 cells and to a much lesser extent in AhR100 cells. 5F 203 and DIM induced miR125b-2 expression and suppressed the expression of stemness-regulating genes such as α6-integrin, a predicted miR125b-2 target. The reduction in stemness-gene expression in MCF-7 cells was attenuated following pretreatment with AhR antagonist CH223191. These data suggest that AhR ligands such as DIM and 5F 203 confer their anticancer actions including those against breast CSCs in an AhR-dependent manner. Our data is expected to provide a rationale for the development of anticancer AhR ligands designed to combat ER+ breast cancer and decrease the risk of relapse. Citation Format: Eileen Brantley, Nicole Mavingire, Jonathan Wooten, Petreena Campbell. Aryl hydrocarbon receptor ligands 5F 203 and 3,3'-Diindolylmethane disrupt mammospheres derived from MCF-7 cells and induce tumor suppressor miR125b-2 expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1304.