ABSTRACT
BACKGROUND: CJM126, 2-(4-aminophenyl) benzothiazole, is a potent inhibitor of human-derived breast carcinoma cell lines. Previous studies have shown that CJM126 elicits concentration-dependent, biphasic growth inhibitory effects against a panel of estrogen receptor-positive and receptor-negative human mammary carcinoma cell lines by a mechanism which has not been fully elucidated. MATERIALS AND METHODS: In an effort to understand the mechanism(s) of resistance to CJM126, the present study used cDNA microarrays (Clontech Laboratories, Inc.) representing 1,176 human cancer-related genes to analyze expression profile changes of two CJM126-resistant cell lines, MCF-710nM126 and MCF-710µM126, previously created by exposing MCF-7 cells to 10 nM and 10 µM CJM126, respectively. RESULTS: Expression changes in the CJM126-resistant MCF-7 cell lines were observed in genes involved in a variety of cell signaling pathways. Gene expression changes common to MCF-710nM126 and MCF-710µM126 cells, as compared to sensitive MCF-7wt cells, were the shut-down of transcription factor Oct-2 and the up-regulation of the negative apoptosis regulator MCL-1, the G1-to-S-phase regulator ubiquitin carrier protein and the GTP-binding protein GST1-HS. These findings indicate the association of a CJM126-resistance phenotype with profound gene transcription dysregulation, decreased apoptotic activity and increased proliferation. Specific changes unique to each of the CJM126-resistant cell lines were also observed. Genes involved in the DNA mismatch-repair pathway, such as MSH2, DNA repair protein RAD51 and damage-specific DNA binding protein were down-regulated in MCF-710nM126, while genes involved in the nucleotide-excision repair pathway, such as ERCC1, RFC and PCNA were overexpressed in MCF-710µM126 Conclusion: The differential changes in the DNA-repair pathways between MCF-710nM126 and MCF-710µM126 cell lines indicate that different processes may have been employed to circumvent the growth inhibition produced by exposure to CJM126. This would also suggest that CJM126 may have concentration-dependent mechanisms of growth inhibition.
