Published online before print July 30, 2009

This Article Full Text Full Text (PDF) Supplemental Material All Versions of this Article: ajpath.2009.081078v1 175/3/1270    most recent Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Google Scholar Articles by Bonofiglio, D. Articles by Andò, S. PubMed PubMed Citation Articles by Bonofiglio, D. Articles by Andò, S.

(American Journal of Pathology. 2009;175:1270-1280.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.081078

Combined Low Doses of PPAR and RXR Ligands Trigger an Intrinsic Apoptotic Pathway in Human Breast Cancer Cells

Daniela Bonofiglio^*, Erika Cione^*, Hongyan Qi^*, Attilio Pingitore^*, Mariarita Perri^*, Stefania Catalano^*, Donatella Vizza^*, Maria Luisa Panno, Giuseppe Genchi^*, Suzanne A.W. Fuqua and Sebastiano Andò^¶

From the Departments of Pharmaco-Biology,^* and Cellular Biology, the Centro Sanitario, and the Faculty of Pharmacy Nutritional and Health Sciences,^¶ University of Calabria, Arcavacata di Rende (Cosenza), Italy; and the Lester and Sue Smith Breast Center, Department of Medicine, Baylor College of Medicine, Houston, Texas

Ligand activation of peroxisome proliferator-activated receptor (PPAR) and retinoid X receptor (RXR) induces antitumor effects in cancer. We evaluated the ability of combined treatment with nanomolar levels of the PPAR ligand rosiglitazone (BRL) and the RXR ligand 9-cis-retinoic acid (9RA) to promote antiproliferative effects in breast cancer cells. BRL and 9RA in combination strongly inhibit of cell viability in MCF-7, MCF-7TR1, SKBR-3, and T-47D breast cancer cells, whereas MCF-10 normal breast epithelial cells are unaffected. In MCF-7 cells, combined treatment with BRL and 9RA up-regulated mRNA and protein levels of both the tumor suppressor p53 and its effector p21^WAF1/Cip1. Functional experiments indicate that the nuclear factor-B site in the p53 promoter is required for the transcriptional response to BRL plus 9RA. We observed that the intrinsic apoptotic pathway in MCF-7 cells displays an ordinated sequence of events, including disruption of mitochondrial membrane potential, release of cytochrome c, strong caspase 9 activation, and, finally, DNA fragmentation. An expression vector for p53 antisense abrogated the biological effect of both ligands, which implicates involvement of p53 in PPAR/RXR-dependent activity in all of the human breast malignant cell lines tested. Taken together, our results suggest that multidrug regimens including a combination of PPAR and RXR ligands may provide a therapeutic advantage in breast cancer treatment.

This article has been cited by other articles:

				M. Ansems, S. Hontelez, M. W. G. Looman, N. Karthaus, P. Bult, J. J. Bonenkamp, J. H. Jansen, F. C. G. J. Sweep, P. N. Span, and G. J. Adema DC-SCRIPT: Nuclear Receptor Modulation and Prognostic Significance in Primary Breast Cancer J Natl Cancer Inst, January 6, 2010; 102(1): 54 - 68. [Abstract] [Full Text] [PDF]