Gene Expression Profiling of 2-(4-Aminophenyl)benzothiazole-resistant MCF-7 Cells Using cDNA Microarrays

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.

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-7^10nM126 and MCF-7^10μM126, previously created by exposing MCF-7 cells to 10 nM and 10 μM CJM126, respectively.

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-7^10nM126 and MCF-7^10μM126 cells, as compared to sensitive MCF-7^wt 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-7^10μM126 Conclusion: The differential changes in the DNA-repair pathways between MCF-7^10nM126 and MCF-7^10μM126 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.