Expression of peroxisome‐proliferator activated receptor‐gamma (PPARγ) and the PPARγ co‐activator, PGC‐1, in human breast cancer correlates with clinical outcomes

Abstract

Peroxisome-proliferator activated receptor-gamma (PPAR␥) belongs to a family of nuclear receptors and acts as receptor for peroxisome-proliferators, steroids, retinoic acids, and polyunsaturated fatty acids. Our study examined the transcript levels of peroxisome-proliferator activated receptorgamma (PPAR␥) and its co-activator (PGC-1) in a cohort of patients with breast cancer. An invasive breast cancer cell, MDA MB 231 exhibited lower level of expression of PPAR␥, compared to non-invasive MCF-7. Breast cancer tissues (n ‫؍‬ 120) exhibited a lower level of PPAR␥ mRNA compared to normal tissues (n ‫؍‬ 25, p ‫؍‬ 0.05). No difference, however, was seen with PGC-1. Although the levels of PPAR␥ and PGC-1 did not correlate with nodal involvement and grade, significantly lower levels of PPAR␥ were seen in TNM3 and TNM4 tumors and from patients with local recurrence and those who died of breast cancer. Lowest level of PGC-1 was also seen in TNM3 and TNM4 tumors and patients who died of breast cancer. We conclude that there is aberrant expression of PPAR␥ and its co-activator, PGC-1, in human breast cancer and low levels of these molecules in cancer tissues are associated with poor clinical outcomes. Peroxisome proliferator activator receptor-gamma (PPAR␥) belongs to a nuclear hormone receptor superfamily that regulates gene expression. 1-3 PPAR␥ contain DNA, lipid and A/B binding domains that recognize DNA response elements in the promoters of their target genes and interact with lipid ligands 4 and prostaglandins (PG J2). 5,6 Ligands for PPAR␥ such as troglitazone, BRL 49653, 15S-hydroxyeicosatetraenoic acid , and 15-deoxy-Delta 12,14-prostaglandin J2 have been shown to inhibit the growth of tumors and induce apoptosis of cancer cells, 7-10 and inhibit colon tumorigenesis in animal models. 11-14 PPAR␥ forms a complex with the PPAR␥ coactivators (PGC-1 and PGC-2) 21,22 and, together with other transcription factors SRC-1 and the CREB binding protein, 23 regulates gene expression, including cyclin regulator p27kip1, cMET protooncogene, and E-cadherin. The inhibition of cell growth by PPAR␥ agonists appears to be via multiple ways, including the inhibition of cyclin D1 15 and increase the level of cell cycle inhibitor P27 kip1 . 16 The proliferation of cancer cells that express PPAR␥ can be inhibited by its ligands and, interestingly, that the effect can be further enhanced by 9-cis retinoic acid, a ligand of RXR alpha. 17 PPAR␥ agonists can also reduce the growth and progressive activities of prostate cancer cells 18,19 and inhibit transcription of genes that are involved in tumor progression, such as the HGF receptor, cMET. 20 Abnormalities in PPAR family members have been implicated in tumorigenesis in animal models and in human cancers. PPAR␣ has been shown to be overexpressed in human prostate cancer. 24,25 Mutation of PPAR␥ has also been reported on colorectal cancer. PPAR␥ can be upregulated by agents such as butyrate in cancer cells. 26 We and others have shown that polyunsaturated fatty acids, such as gamma linol...

PGC-1α induces apoptosis in human epithelial ovarian cancer cells through a PPARγ-dependent pathway

“…In this study, we first demonstrated that PGC-1α mRNA level was significantly decreased in late-stage human epithelial ovarian cancer compared with normal ovarian tissues. This finding is also consistent with others reports and our own studies showing that PGC-1α is downregulated in breast cancer [12,13], colon cancer [14], liver cancer and hypothyroid cancer (data not shown). Therefore, a better understanding of PGC-1α's effect on epithelial ovarian cancer may have important implications for the treatment of this disease in clinics.…”

“…Recent report shows that the expression of PPARγ is significantly enhanced in the late-stage epithelial ovarian carcinoma, indicating that PPARγ contributes significantly to the onset and progression of ovarian cancer [33]. Because the levels of PPARγ and the PPARγ coactivator, PGC-1α, are always linked to clinical outcome in patients with a variety of human cancers [12][13][14], it is reasonable to suspect that PGC-1α may also play a pivotal role in the pathogenic development of epithelial ovarian cancer. However, no correlation has been established for the possible involvement of PGC-1α in ovarian cancer.…”

“…It plays important roles in the regulation of adaptive thermogenesis in brown fat and muscle [8], muscle fiber-type switching in muscle [9], gluconeogenesis in liver [10] and insulin secretion in islets [11]. More recently, it has been found that the expression level of PGC-1α decreased in certain cancer tissues such as breast [12,13] and colon cancers [14], suggesting that PGC-1α may be involved in the pathogenesis of cancer. In addition, the decrease of PGC-1α is always linked to the variation of peroxisome proliferator-activated receptor gamma (PPARγ) expression level [12][13][14].…”

“…More recently, it has been found that the expression level of PGC-1α decreased in certain cancer tissues such as breast [12,13] and colon cancers [14], suggesting that PGC-1α may be involved in the pathogenesis of cancer. In addition, the decrease of PGC-1α is always linked to the variation of peroxisome proliferator-activated receptor gamma (PPARγ) expression level [12][13][14]. PPARγ, a member of the nuclear receptor superfamily, forms a complex with coactivator PGCs to npg regulate gene expression [8,15,16].…”

Increased PTEN expression due to transcriptional activation of PPARγ by Lovastatin and Rosiglitazone

“…23 Additionally, PPARg has been shown to be underexpressed and correlates with clinical outcomes in breast cancer patients. 24 In nude mouse and rat models, treatment of breast cancer cells with PPARg agonists inhibits tumor progression within the breast tissue. 25,26 There is also an overlap of solid tumor data where both PPARg and PTEN have been implicated in its pathogenesis.…”