NOVEL ESTROGENIC ACTION OF THE PESTICIDE-RESIDUE BETA-HEXACHLOROCYCLOHEXANE IN HUMAN BREAST-CANCER CELLS

The estrogenic action of some persistent organochlorine pesticide resi dues may play a role in the progression of hormonally responsive tumor s of the breast and uterus. The prototypical xenoestrogen o,p'-dichlor odiphenyltrichloroethane (o,p'-DDT) acts by binding and activating the estrogen receptor (ER). The present study focuses attention on the me chanisms through which another organochlorine compound, beta-hexachlor ocyclohexane (beta-HCH), exerts estrogen-like effects in human breast cancer cells. Both o,p'DDT and beta-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 c ompounds produced an increase in the steady state level of pS2 mRNA in MCF-7 cells. These responses were equal in magnitude to the maximal e ffect of estradiol, and they were inhibited by inclusion of the anties trogen ICI164384. On the other hand, when tested in a competitive bind ing assay, beta-HCH did not displace 17 beta-[H-3]estradiol from the E R even at a concentration that was 40,000-fold higher than the tracer steroid. Furthermore, nuclear retention of the ER during homogenizatio n procedures was induced by a 2- or 24-h treatment of MCF-7 cells with o,p'-DDT and 17 beta-estradiol but not by treatment with beta-HCH; th is indicates that beta-HCH nether activates the ER, nor is it converte d intracellularly to an ER ligand. Transcriptional activation by beta- HCH occurs in estrogen-responsive GH3 rat pituitary tumor cells transf ected with a luciferase reporter construct driven by a complex 2500-bp portion of the PRL gene promoter; this trans-activation response is i nhibited by inclusion of ICI164384. However, beta-HCH is ineffective i n stimulating a reporter construct driven only by a consensus estrogen response element and a minimal promoter derived from the herpes simpl ex virus thymidine kinase gene. Thus, beta-HCH cannot act on a simple, single estrogen response element; rather, it requires the combinatori al regulation found in a complex promoter. These data are consistent w ith the notion that beta-HCH stimulation of cell proliferation and gen e expression is ER dependent, but its action is not through the classi c pathway of binding and activating the ER. beta-HCH may represent a n ew class of xenobiotic that produces estrogen-like effects through non classic mechanisms and, therefore, may be of concern with regard to br east and uterine cancer risk.