Novel estrogenic action of the pesticide residue β-hexachlorocyclohexane in human breast cancer cells

Rosemary Steinmetz, Peter C.M. Young, Andrea Caperell-Grant, Edward A. Gize, Burra V. Madhukar, Nira Ben-Jonathan, Robert M. Bigsby

Research output: Contribution to journalArticle

107 Scopus citations

Abstract

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, β-hexachlorocyclohexane (β-HCH), exerts estrogen-like effects in human breast cancer cells. Both o,p′DDT and β-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, β-HCH did not displace 17β-[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 17β-estradiol but not by treatment with β-HCH; this indicates that β-HCH nether activates the ER, nor is it converted intracellularly to an ER ligand. Transcriptional activation by β-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, β-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, β-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 β-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. β-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.

Original languageEnglish (US)
Pages (from-to)5403-5409
Number of pages7
JournalCancer Research
Volume56
Issue number23
StatePublished - Dec 1 1996

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Steinmetz, R., Young, P. C. M., Caperell-Grant, A., Gize, E. A., Madhukar, B. V., Ben-Jonathan, N., & Bigsby, R. M. (1996). Novel estrogenic action of the pesticide residue β-hexachlorocyclohexane in human breast cancer cells. Cancer Research, 56(23), 5403-5409.