Suppression of breast cancer by chemical modulation of vulnerable zinc fingers in estrogen receptor.
Current antiestrogen therapy for breast cancer is limited by the mixed estrogenic and antiestrogenic activity of selective estrogen receptor modulators. Here we show that the function of zinc fingers in the estrogen receptor DNA-binding domain (DBD) is susceptible to chemical inhibition by electrophilic disulfide benzamide and benzisothiazolone derivatives, which selectively block binding of the estrogen receptor to its responsive element and subsequent transcription. These compounds also significantly inhibit estrogen-stimulated cell proliferation, markedly reduce tumor mass in nude mice bearing human MCF-7 breast cancer xenografts, and interfere with cell-cycle and apoptosis regulatory gene expression. Functional assays and computational analysis support a molecular mechanism whereby electrophilic agents preferentially disrupt the vulnerable C-terminal zinc finger, thus suppressing estrogen receptor-mediated breast carcinoma progression. Our results provide the proof of principle for a new strategy to inhibit breast cancer at the level of DNA binding, rather than the classical antagonism of estrogen binding.
Wang
Li Hua
LH
Basic Research Program, SAIC-Frederick, National Cancer Institute-Frederick, National Institutes of Health, PO Box B, Frederick, Maryland 21702, USA. lhwang@ncifcrf.gov
Yang
Xiao Yi
XY
Zhang
Xiaohu
X
Mihalic
Kelly
K
Fan
Ying-Xin
YX
Xiao
Weihua
W
Howard
O M Zack
OM
Appella
Ettore
E
Maynard
Andrew T
AT
Farrar
William L
WL
D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001483:Base Sequence; D001549:Benzamides / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D017931:DNA Primers; D004273:DNA, Neoplasm / Q000378:metabolism; D020847:Estrogen Receptor Modulators / Q000627:therapeutic use*; D006801:Humans; D013844:Thiazoles / Q000627:therapeutic use*; D015533:Transcriptional Activation; D016335:Zinc Fingers
D018931:Antineoplastic Agents, Hormonal; D001549:Benzamides; D017931:DNA Primers; D004273:DNA, Neoplasm; D020847:Estrogen Receptor Modulators; D013844:Thiazoles; C466948:benzisothiazole; C037689:benzamide