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

This study was undertaken to investigate the influence of the peroxisome pr oliferator-activated receptor gamma (PPAR gamma) agonists on the proliferat ion, apoptosis and tumorigenesis of breast cancer cells. PPAR gamma investi gation has been largely restricted to adipose tissue, where it plays a key role in differentiation, but recent data reveal that PPAR gamma is expresse d in several transformed cells. However, the function of PPAR gamma activat ion in neoplastic cells is unclear. Activation of PPAR gamma with the known prostanoid agonist 15-deoxy-Delta 12,14-prostaglandin J(2) (15dPGJ(2)) 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 inhibit ion of cell cycle progression. Addition of 15dPGJ(2) was not associated wit h an increase in cellular differentiation, as has been seen in other neopla stic cells, but rather induction of cellular events associated with program med cell death, apoptosis, Video time-lapse microscopy revealed that 15dPGJ (2) induced morphological changes associated with apoptosis, including cell ular rounding, blebbing, the production of echinoid spikes, blistering and cell lysis, In contrast, TGZ caused only a modest induction of apoptosis, T hese results were verified by histochemistry using the specific DNA stain D API to observe nuclear condensation, a marker of apoptosis, Finally, a brie f exposure of MDA-MB-231 cells to 15dPGJ(2) initiated an irreversible apopt otic pathway that inhibited the growth of tumors in a nude mouse model. The se findings illustrate that induction of apoptosis may be the primary biolo gical response resulting from PPAR gamma activation in some breast cancer c ells and further suggests a potential role for PPAR gamma ligands for the t reatment of breast cancer.