Divergent mechanisms for loss of Ah-responsiveness in benzo[a]pyrene- and AdriamycinR-resistant MCF-7 cells

The intracellular aryl hydrocarbon receptor (AhR) mediates signal transduction by environmental pollutants such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and benzo[a] pyrene by functioning as a ligand-activated transcription factor. We have investigated AhR signaling in sublines of the human breast cancer cell line MCF-7 selected for resistance to Adriamycin(R) (Adr(R)) and benzo[a]pyrene (BPR). Previously we reported that AdrR cells have a loss of estrogen receptor (ER) expression and are Ah-nonresponsive. Here we show that AhR mRNA and protein are expressed at normal levels in Adr(R) cells, and the activated AhR complex is functionally capable of binding a xenobiotic responsive element. In MCF-7 cells AhR was depleted to 15% of normal levels after 4 hr TCDD treatment; however, 45% of AhR remained in Adr(R) cells during this time course. In BPR cells AhR mRNA levels were found to be decreased relative to wild-type cells, which led to decreased AhR protein levels and DNA-binding activity. Cellular ER content has been shown to correlate with Ah-responsiveness in human breast cancer cell lines. BPR cells were found to be ER-positive, although chronic (BPR cells) and acute (24 hr) exposure to benzo[a]pyrene led to significantly lower ER protein levels in MCF-7 cells. We conclude that loss of Ah-responsiveness occurs by different mechanisms in xenobiotic-resistant MCF-7 sublines: AhR mRNA is down-regulated in BPR cells, whereas Adr(R) cells are deficient in AhR signaling by a mechanism unrelated to AhR expression and activity. BIOCHEM PHARMACOL 57;11:1253-1263, 1999. (C) 1999 Elsevier Science Inc.