Peroxisome proliferator-activated receptor γ in human breast carcinoma: a modulator of estrogenic actions

Abstract

It has been reported that agonists of peroxisome proliferator-activated receptor g (PPARg) inhibit proliferation of breast carcinoma cells, but the biological significance of PPARg remains undetermined in human breast carcinomas. Therefore, we immunolocalized PPARg in 238 human breast carcinoma tissues. PPARg immunoreactivity was detected in 42% of carcinomas, and was significantly associated with the status of estrogen receptor (ER) a, ERb, progesterone receptor, retinoic X receptors, p21 or p27, and negatively correlated with histological grade or cyclooxygenase-2 status. PPARg immunoreactivity was significantly associated with an improved clinical outcome of breast carcinoma patients by univariate analysis, and multivariate analysis demonstrated that PPARg immunoreactivity was an independent prognostic factor for overall survival in ERa-positive patients. We then examined possible mechanisms of modulation by PPARg on estrogenic actions in MCF-7 breast carcinoma cells. A PPARg activator, 15-deoxy-D 12,14 -prostaglandin J 2 (15d-PGJ 2 ), significantly inhibited estrogen-responsive element-dependent transactivation by estradiol in MCF-7 cells, which was blocked by addition of a PPARg antagonist GW9662. Subsequent study, employing a custom-made microarray focused on estrogenresponsive genes, revealed that mRNA expression was significantly regulated by estradiol in 49 genes, but this significance vanished on addition of 15d-PGJ 2 in 16 out of 49 (33%) genes. These findings were confirmed by real-time PCR in 11 genes. 15d-PGJ 2 significantly inhibited estrogenmediated proliferation of MCF-7 cells, and caused accumulation of p21 and p27 protein. These results suggest that PPARg is mainly expressed in well-differentiated and ER-positive breast carcinomas, and modulates estrogenic actions.

Correlation of thyroid hormone, retinoid X, peroxisome proliferator-activated, vitamin D and oestrogen/progesterone receptors in breast carcinoma

“…In contrast to our previous findings (35), which demonstrated a correlation between PPAR and positive lymph node involvement, discrepant results have also been reported (34). These current conflicting results need to be resolved in larger trials.…”

“…For PPARγ, an inverse association with tumour size was found (34). In contrast to our previous findings (35), which demonstrated a correlation between PPAR and positive lymph node involvement, discrepant results have also been reported (34).…”

Peroxisome Proliferator-Activated Receptor γ Is a Zac Target Gene Mediating Zac Antiproliferation

“…Consistent with our results, showing that Zac antiproliferation is mediated by PPARg, both proteins play a role in tumor suppression of breast cancer (4,(42)(43)(44) and pituitary adenomas (40,41,45,46). Acromegalic patients suffering from growth hormone (GH)-producing pituitary tumors are routinely treated with somatostatin analogues, such as octreotide.…”

Peroxisome proliferator-activated receptor gamma activates fas ligand gene promoter inducing apoptosis in human breast cancer cells

“…Several antineoplastic effects, such as induction of apoptosis and differentiation, have been described as a result of PPARc-mediated action both in vitro and in vivo [4][5][6][7][8][9][10], although the molecular mechanisms by which PPARc causes these effects remain to be fully elucidated. PPARc is able to be activated by ligands of physiological or pharmacological origin [11].…”