Novel therapeutic approach: ligands for PPARgamma and retinoid receptors induce apoptosis in bcl-2-positive human breast cancer cells.
Effective treatment of tumors is often associated with activation of the endogenous apoptosis pathways. We have studied eight breast cancer cell lines (MCF-7, BT20, BT474, MDA-MB-231, MDA-MB-436, SKBR3, T-47D, ZR-75-1) possessing a variety of genetic defects. The clonogenic growth of breast cancer cell lines was inhibited by a ligand for PPARgamma (troglitazone, TGZ) combined with a ligand for either retinoid X receptor (RXR) (LG10069) (4/8 cell lines), RAR (ATRA) (5/8 cell lines) or RAR/RXR and RXR/RXR (9-cis-RA) (5/8 cell lines) independent of their expression of bcl-2, bag-1, ERalpha, and p53. The cell lines (MCF-7, T-47D, ZR-75-1), which expressed both BRCA1 and p27, were extremely sensitive to the inhibitory effect of the combination of TGZ and either ATRA or 9-cis-RA (ED90, 2-5 x 10(-11) M). However, only MCF-7, MDA-MB-231, and ZR-75-1 cells, which expressed a high level of bcl-2 protein, underwent apoptosis when exposed to the combination of TGZ and either ATRA or 9-cis-RA. Importantly, this effect was independent of expression levels of p53, ERalpha, HER-2/neu, bag-1, and BRCA1. Therefore, the combination of ligands for PPARgamma and retinoid receptors may have a therapeutic role for breast cancer.
Division of Hematology/Oncology, School of Medicine Charité, Humboldt University, Berlin, Germany. elena.elstner@charite.de
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Elstner
E A
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Williamson
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Zang
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Fritz
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Heber
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M
Fenner
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Possinger
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Koeffler
D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D004268:DNA-Binding Proteins; D005260:Female; D006801:Humans; D008024:Ligands; D008830:Microbodies; D009687:Nuclear Proteins; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors*; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors* / Q000502:physiology*; D012097:Repressor Proteins; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D016335:Zinc Fingers
D004268:DNA-Binding Proteins; D008024:Ligands; D009687:Nuclear Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; D014157:Transcription Factors