Ah receptor agonists as endocrine disruptors: antiestrogenic activity and mechanisms

Abstract

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and related compounds induce a broad spectrum of biochemical and toxic responses and disrupt multiple endocrine pathways. Research in this laboratory has focused on characterizing aryl hydrocarbon receptor (AhR)-mediated antiestrogenicity in the rodent uterus and mammary and in human breast cancer cells. TCDD inhibits multiple estrogen (E2)-induced responses in these tissues including development or growth of human mammary and endometrial cancer cells, carcinogen-induced mammary cancer in rats, and mammary cancer in mice bearing breast cancer cell xenografts. The mechanisms of AhR-mediated antiestrogenicity are complex; however, studies on the molecular biology of cross-talk between the AhR and estrogen-receptor (ER) signaling pathways have been initiated using several E2-regulated genes as models. The results indicate that the nuclear AhR complex targets specific genomic core inhibitory dioxin responsive elements (iDREs) in promoter regions of some E2-responsive target genes to inhibit hormone-induced transactivation. The pS2, cathepsin and c-fos genes have functional iDREs, whereas the iDRE in the progesterone receptor gene promoter was not functional. Research has also focused on development of AhR-based antiestrogens which inhibit mammary tumor development and growth but do not exhibit prototypical AhR-induced toxic responses.

Introduction

Polychlorinated biphenyls (PCBs), dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) are industrial compounds or by-products of industrial and combustion processes that have been identified in almost every component of the global ecosystem including fish, wildlife human adipose tissue, milk and serum (Safe, 1995). 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), the most toxic halogenated hydrocarbon, induces a broad spectrum of biochemical and toxic responses in experimental animals and mammalian cells in culture and many of these responses are also dependent on the target organ, age, sex, species and strain of laboratory animal. Poland et al. (1976)initially discovered that TCDD and related compounds bound to an intracellular cytosolic protein designated as the aryl hydrocarbon receptor (AhR). Subsequent studies in several laboratories have demonstrated that the AhR is a ligand-activated nuclear transcripter factor which binds with high affinity to TCDD (K_D<1 nM); however, an endogenous ligand has not been identified. The nuclear AhR complex is a heterodimer containing the AhR and AhR nuclear translocater (Arnt) proteins which are members of the basic helix–loop–helix family of nuclear transcription factors. AhR-mediated transactivation was initially investigated using the CYP1A1 gene promoter as a model, and ligand-induced expression of this gene requires binding of the nuclear AhR complex with distal dioxin responsive elements (DREs) that contain a core pentanucleotide sequence required for binding the AhR complex and flanking sequences necessary for transactivation (Whitlock, 1993):

$$\text{5′−}\text{T/G}\text{n}\text{GCGTG}\text{A/C}\text{G/C}\text{A}\text{−3′}$$$$\text{(}\text{core}\text{pentanucleotide}\text{).}$$