Abstract
Inflammatory and invasive breast cancers are aggressive and require better understanding for the development of new treatments and more accurate prognosis. Here, we detected high expression of PPARα in human primary inflammatory (SUM149PT) and highly invasive (SUM1315MO2) breast cancer cells, and tissue sections of human breast cancer. PPARα ligands are clinically used to treat dyslipidemia. Among lipid lowering drugs clofibrate, fenofibrate and WY14643, clofibrate showed high chemo-sensitivity towards breast cancer cells. Clofibrate treatment significantly induced PPARα DNA binding activity, and remarkably reduced cyclooxygenase-2/PGE2 and 5-lipoxygenase/LTB4 inflammatory pathways. Clofibrate treatment reduced the proliferation of breast cancer cells probably by inhibiting NF-κB and ERK1/2 activation, reducing cyclinD1, cyclinA, cyclinE, and inducing pro-apoptotic P21 levels. Surprisingly, the expression of lipogenic pathway genes including SREBP-1c (sterol regulatory element-binding protein-1c), HMG-CoA synthase, SPTLC1 (serine palmitoyltransferase long-chain), and Acyl-CoA oxidase (ACO) decreased with a concurrent increase in fatty acid oxidation genes such as CPT-1a (carnitine palmitoyltransferase 1a) and SREBP-2 (Sterol regulatory element-binding protein-2). Clofibrate treatment induced secretion of free fatty acids and effectively decreased the level of phosphorylated active form of fatty acid synthase (FASN), an enzyme catalyzing de novo synthesis of fatty acids. High level of coactivators steroid receptor coactivator-1 (SRC-1) and histone acetylase CBP-300 (CREB binding protein-300) were observed in the nuclear complexes of clofibrate treated breast cancer cells. These findings implicate that stimulating PPARα by safe, well-tolerated, and clinically approved clofibrate may provide a safer and more effective strategy to target the signaling, lipogenic, and inflammatory pathways in aggressive forms of breast cancer.
Highlights
IntroductionTranscriptional activity of peroxisome proliferator-activated receptors (PPARs) is controlled by both the availability of PPAR ligands and by interactions with protein coactivators and corepressors known as “coregulators” that are recruited into transcriptional complexes and subsequently activate/suppress gene expression [4]
Breast cancer is the most common cancer and the second leading cause of death from malignancy in women in the United States
Breast cancer cells express higher levels of PPARα as compared to human mammary epithelial cells (HMEC) cells Compared to HMEC cells, increased expression of PPARα was observed in SUM149PT (3.9-fold) and SUM1315MO2 (3.7-fold) breast cancer cells (Figure 1A)
Summary
Transcriptional activity of PPARs is controlled by both the availability of PPAR ligands and by interactions with protein coactivators and corepressors known as “coregulators” that are recruited into transcriptional complexes and subsequently activate/suppress gene expression [4] Because coactivators such as steroid receptor coactivator-1 (SRC1), p300 kDa/CREB binding protein (p300/CBP) affect chromatin configuration and recruit protein complexes to serve as a link between the PPAR and the transcriptional apparatus, they are critical fine-tuning proteins for many aspects of classic PPAR transcriptional function and when coregulator expression goes wrong, pathogenesis can occur. There is need to improve insight into the specific mechanisms and pathways of endogenous PPARα activation in order to better link the functional consequences of PPARα activation to induction of PPARα responsive target genes
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