Transcriptional activation of cathepsin D gene expression by 17β-estradiol:: mechanism of aryl hydrocarbon receptor-mediated inhibition

17 beta -estradiol (E2) induces cathepsin D gene expression in MCF-7 human breast cancer cells and this response is inhibited by aryl hydrocarbon receptor (AhR) agonists, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCD D). Analysis of the cathepsin D gene promoter initially identified a pentanucleotide GCGTG core dioxin responsive element (DRE) that blocked E2 action by inhibiting formation of a transcriptionally active estrogen receptor (ER)-Sp1 complex. A second functional downstream inhibitory DRE (iDRE2) (- 130 to - 126) has now been identified in the cathepsin D gene promoter and inhibition of E2-induced transactivation involves inhibitory AhR crosstalk with the E2-responsive adenovirus major late promoter element (MLPE) at - 124 to - 104 in the cathepsin D gene promoter. The MLPE site primarily binds USF1/USF2 and ER alpha, and gel mobility shift and DNA footprinting assays show that the AhR complex decreases binding of these transcription factors to the MLPE. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.