A serious obstacle to successful treatment of estrogen receptor (ER)-positive human breast cancer is cell resistance to tamoxifen (TAM) therapy. Here we show that the electrophile disulfide benzamide (DIBA), an ER zinc finger inhibitor, blocks ligand-dependent and -independent cell growth of TAM-resistant breast cancer in vitro and in vivo. Such inhibition depends on targeting disruption of the ER DNA-binding domain and its communication with neighboring functional domains, facilitating ERα dissociation from its coactivator AIB1 and concomitant association with its corepressor NCoR bound to chromatin. DIBA does not affect phosphorylation of HER2, MAPK, AKT, and AIB1, suggesting that DIBA-modified ERα may induce a switch from agonistic to antagonistic effects of TAM on resistant breast cancer cells.
Bibliographical noteFunding Information:
We are very grateful to Dr. A.T. Maynard for helpful discussion in the initial stage, Dr. P. Chambon for kindly providing ER expression plasmids, Drs. J. Hartley and D. Esposito for help making pSG5-HEZF constructs, Drs. M. R. Anver, S. Lawrence and K. Rogers for help in pathology, Dr. O. M. Z. Howard for help in animal experiments, Drs. K. Noer and W. Li for help in analysis of cell cycles, and Mr. B. Harris and E. Cho for help in image analysis. This research was supported by the Intramural Research Program of the Center for Cancer Research, NCI/NIH, and also funded in part with federal funds from the NCI under contract # NO1-CO-12400.