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 AdriamycinR (AdrR) and benzo[a]pyrene (BP(R)). 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 AdrR 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 AdrR cells during this time course. In BP(R) 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. BP(R) cells were found to be ER-positive, although chronic (BP(R) 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 BP(R) cells, whereas AdrR cells are deficient in AhR signaling by a mechanism unrelated to AhR expression and activity.
Caruso
J A
JA
McGill Center for Translational Research in Cancer, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec, Canada.
Batist
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D000970:Antineoplastic Agents / Q000494:pharmacology*; D001564:Benzo(a)pyrene / Q000494:pharmacology*; D002273:Carcinogens / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D004273:DNA, Neoplasm / Q000378:metabolism; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D006801:Humans; D008024:Ligands; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D018336:Receptors, Aryl Hydrocarbon / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D002273:Carcinogens; D004273:DNA, Neoplasm; D008024:Ligands; D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D001564:Benzo(a)pyrene; D004317:Doxorubicin