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Carcinogenesis, Vol. 20, No. 10, 1905-1911, October 1999
© 1999 Oxford University Press

Cancer Biology

Influence of J series prostaglandins on apoptosis and tumorigenesis of breast cancer cells

Carl E. Clay1, Andrew M. Namen1, Gen-ichi Atsumi1, Mark C. Willingham2, Kevin P. High1, Timothy E. Kute2, Anthony J. Trimboli1, Alfred N. Fonteh1, Paul A. Dawson1 and Floyd H. Chilton1,3,4

1 Department of Internal Medicine,
2 Department of Pathology and
3 Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston Salem,NC 27157-1054, USA

This study was undertaken to investigate the influence of the peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) agonists on the proliferation, apoptosis and tumorigenesis of breast cancer cells. PPAR{gamma} investigation has been largely restricted to adipose tissue, where it plays a key role in differentiation, but recent data reveal that PPAR{gamma} is expressed in several transformed cells. However, the function of PPAR{gamma} activation in neoplastic cells is unclear. Activation of PPAR{gamma} with the known prostanoid agonist 15-deoxy-{Delta}12,14-prostaglandin J2 (15dPGJ2) or the thiazolidinedione (TZD) agonist troglitazone (TGZ) attenuated cellular proliferation of the estrogen receptor-negative breast cancer cell line MDA-MB-231, as well as the estrogen receptor-positive breast cancer cell line MCF-7. This was marked by a decrease in total cell number and by an inhibition of cell cycle progression. Addition of 15dPGJ2 was not associated with an increase in cellular differentiation, as has been seen in other neoplastic cells, but rather induction of cellular events associated with programmed cell death, apoptosis. Video time-lapse microscopy revealed that 15dPGJ2 induced morphological changes associated with apoptosis, including cellular rounding, blebbing, the production of echinoid spikes, blistering and cell lysis. In contrast, TGZ caused only a modest induction of apoptosis. These results were verified by histochemistry using the specific DNA stain DAPI to observe nuclear condensation, a marker of apoptosis. Finally, a brief exposure of MDA-MB-231 cells to 15dPGJ2 initiated an irreversible apoptotic pathway that inhibited the growth of tumors in a nude mouse model. These findings illustrate that induction of apoptosis may be the primary biological response resulting from PPAR{gamma} activation in some breast cancer cells and further suggests a potential role for PPAR{gamma} ligands for the treatment of breast cancer.

Abbreviations: ATRA, all-trans-retinoic acid; DAPI, 4',6-diamidine-2'-phenylindole diHCl; {Delta}12-PGJ2, {Delta}12-prostaglandin J2; 15dPGJ2, 15-deoxy-{Delta}12,14-prostaglandin J2; PBS, phosphate-buffered saline; PPAR{gamma}, peroxisome proliferator-activated receptor {gamma}; PG, prostaglandin; RAR, retinoic acid receptor; RXR, retinoid X receptor; TGZ, troglitazone; TZD, thiazolidinedione.

4 To whom correspondence should be addressed Email: fchilton{at}wfubmc.edu


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