NEW YORK (Reuters Health) - Modulation of estrogen receptor zinc finger function by disulfide benzamide and benzisothiazolone derivatives suppresses breast cancer growth in vitro and in nude mice, according to a report in the December 14th advance online publication of Nature Medicine.
Zinc fingers in the estrogen receptor’s DNA-binding domain (DBD) stabilize the structures of the estrogen receptor-DNA complex, the authors explain, so that disruption of these zinc fingers could have a critical impact on estrogen-receptor mediated transcription and, thereby, on the growth of breast cancer cells.
Dr. William L. Farrar from National Cancer Institute-Frederick, Frederick, Maryland and colleagues investigated whether electrophilic agents, including benzamide and benzisothiazolone derivatives, could inhibit estrogen receptor DBD function and suppress the growth of breast cancer cell lines and of breast cancers explants in nude mice.
Two such compounds, DIBA and BITA, effectively blocked the growth of estrogen receptor-positive breast cancer cells in culture, the authors report. Moreover, treatment with these compounds markedly reduced the volume of breast carcinoma xenografts in nude mice and prevented significant invasion into surrounding skin tissue.
DIBA markedly decreased the expression of the cell-cycle genes E2F1 and E2F2 and the antiapoptosis genes BCL-2 and BCL2L1, the report indicates.
Further experiments confirmed the selective reaction of the two compounds with estrogen receptor DBD zinc fingers and their lack of influence on the endogenous activities of other nuclear receptors, the researchers note, “further confirming that DIBA and BITA selectively inhibit estrogen receptor-mediated breast cancer cell growth by inhibiting estrogen receptor zinc finger function.”
DIBA and BITA did not affect the growth of estrogen receptor-negative breast cancer cells or estrogen receptor-negative breast carcinoma xenografts in nude mice, the results indicate.
“This research represents a new type of molecular intervention strategy born from the collaboration of molecular modeling studies, biochemistry, and molecular biology reflective of the great advances in all fields,” Dr. Farrar told Reuters Health. “This type of integrated approach, rather than high throughput screening, is the future of drug development.”
“The DIBA and BITA are ‘lead’ compounds, whose in vivo toxicity is not totally known,” Dr. Farrar said. “We have already moved to a more complete structure-function analysis that has found simpler compounds with better solubility and pharmacological properties.”
“Almost all estrogen receptor-positive breast cancer patients cells eventually become tamoxifen-resistant,” Dr. Farrar added. “Accordingly, our new models are using tamoxifen-resistant estrogen receptor-positive cells and comparing directly our ‘new’ zinc ejection compounds directly against tamoxifen-resistant cell lines.”
Nat Med 14 December 2003;doi:10.1038/nm969.
MeSH Headings:Breast Neoplasms: Neoplasms: Neoplasms by Site: Receptors, Estrogen: Receptors, Steroid: Transcription Factors: Zinc Fingers: Protein Structure, Secondary: Receptors, Cytoplasmic and Nuclear: Amino Acid Motifs: DiseasesCopyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
