The nuclear receptor, peroxisome proliferator-activated receptor gamma (PPARγ), is expressed in various cancer cells including breast, prostate, colorectal and cervical examples. An endogenous ligand of PPARγ, 15-deoxy-Δ12,14 prostaglandin J2 (PGJ2), is emerging as a potent anticancer agent but the exact mechanism has not been fully elucidated, especially in breast cancer. The present study compared the anticancer effects of PGJ2 on estrogen receptor alpha (ERα)-positive (MCF-7) and ERα-negative (MDA-MB-231) human breast cancer cells. Based on the reported signalling cross-talk between PPARγ and ERα, the effect of the ERα ligand, 17β-estradiol (E2) on the anticancer activities of PGJ2 in both types of cells was also explored. Here we report that PGJ2 inhibited proliferation of both MCF-7 and MDA-MB-231 cells by inducing apoptotic cell death with active involvement of mitochondria. The presence of E2 potentiated PGJ2-induced apoptosis in MCF-7, but not in MDA-MB-231 cells. The PPARγ antagonist, GW9662, failed to block PGJ2-induced activities but potentiated its effects in MCF-7 cells, instead. Interestingly, GW9662 also proved capable of inducing apoptotic cell death. It can be concluded that E2 enhances PPARγ-independent anticancer effects of PGJ2 in the presence of its receptor.