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Novel Estrogenic Action of the Pesticide Residue ß-Hexachlorocyclohexane in Human Breast Cancer Cells¹

Departments of Obstetrics and Gynecology [R. S., P. C. M. Y., A. C-G., R. M. B.], Physiology and Biophysics [E. A. G., R. M. B.], and Pharmacology and Toxicology [B. V. M.]. Indiana University School of Medicine, Indianapolis, Indiana 46202, and Department of Cell Biology, Neurobiology, and Anatomy, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267 [N. B-J.]

The estrogenic action of some persistent organochlorine pesticide residues may play a role in the progression of hormonally responsive tumors of the breast and uterus. The prototypical xenoestrogen o,p'-dichlorodiphenyltrichloroethane (o,p'-DDT) acts by binding and activating the estrogen receptor (ER). The present study focuses attention on the mechanisms through which another organochlorine compound, ß-hexachlorocyclohexane (ß-HCH), exerts estrogen-like effects in human breast cancer cells. Both o,p'DDT and ß-HCH stimulated proliferation in a dose-dependent manner in the ER-positive cell lines MCF-7 and T47D but not in the ER-negative lines MDA-MB231, MDA-MB468, and HS578T. Both compounds produced an increase in the steady state level of pS2 mRNA in MCF-7 cells. These responses were equal in magnitude to the maximal effect of estradiol, and they were inhibited by inclusion of the antiestrogen ICI164384. On the other hand, when tested in a competitive binding assay, ß-HCH did not displace 17ß-[³H]estradiol from the ER even at a concentration that was 40,000-fold higher than the tracer steroid. Furthermore, nuclear retention of the ER during homogenization procedures was induced by a 2- or 24-h treatment of MCF-7 cells with o,p'-DDT and 17ß-estradiol but not by treatment with ß-HCH; this indicates that ß-HCH nether activates the ER, nor is it converted intracellularly to an ER ligand.

Transcriptional activation by ß-HCH occurs in estrogen-responsive GH3 rat pituitary tumor cells transfected with a luciferase reporter construct driven by a complex 2500-bp portion of the PRL gene promoter; this trans-activation response is inhibited by inclusion of ICI164384. However, ß-HCH is ineffective in stimulating a reporter construct driven only by a consensus estrogen response element and a minimal promoter derived from the herpes simplex virus thymidine kinase gene. Thus, ß-HCH cannot act on a simple, single estrogen response element; rather, it requires the combinatorial regulation found in a complex promoter.

These data are consistent with the notion that ß-HCH stimulation of cell proliferation and gene expression is ER dependent, but its action is not through the classic pathway of binding and activating the ER. ß-HCH may represent a new class of xenobiotic that produces estrogen-like effects through nonclassic mechanisms and, therefore, may be of concern with regard to breast and uterine cancer risk.

¹ This work was supported in part by NIH Grants NS13243 (N. B-J.), US Army DAMD 17-94-J-4452 (N. B-J.), and HD23244 (R. M. B.).

² To whom requests for reprints should be addressed, at Department of Obstetrics and Gynecology, Indiana University School of Medicine, 1001 West Walnut Street (MF102), Indianapolis, IN 46202-5196.

Received 6/24/96. Accepted 10/ 2/96.

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