Implications of a peroxisome proliferator-activated receptor alpha (PPARα) ligand clofibrate in breast cancer

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.

Osteoprotegerin rich tumor microenvironment: implications in breast cancer

“…It also serves as a potential diagnostic and prognostic biomarker as it is secreted in the blood of patients with breast, prostate, colon and ovarian cancers compared with normal healthy subjects [69]. In our recent study we demonstrated that compared to HMEC, SUM149PT and SUM1315MO2 breast cancer cells express increased level of FASN [70]. We have several interesting findings in the context of paracrine signaling in the OPG rich breast cancer microenvironment that drives carcinogenesis via inducing and sustaining inflammatory cycloxygenase-2 (COX-2) and lipogenic FASN in an invasive breast cancer setting (Figure 3) (unpublished results).…”

The Involvement of PPARs in the Peculiar Energetic Metabolism of Tumor Cells

“…Unlike what stated so far, PPARα activation could be useful to fight tumor progression in some tissue, as evidenced in melanoma [78]; in addition to positively affect transcription of FAO enzymes, PPARα is able to decrease transcription of fatty acid synthesis genes. Chandran et al reported favourable results on the protective roles of the PPARα agonist, clofibrate, in discouraging breast cancer inflammation and invasion [121]. They used two triple negative breast cancer cell line, SUM149PT and SUM1315MO2, the first from invasive ductal carcinoma of a patient with inflammatory breast cancer, and the second from highly invasive breast cancer specimen of patient with skin metastasis.…”

“…SREBP-1c (sterol regulatory element binding protein 1c) plays an important role in regulation of de novo fatty acid synthesis, while its cognate SREBP-2 regulates genes of the cholesterol metabolism [123], SREBPs pathway has a key role in fatty acid de novo synthesis of prostate cancer cells [124]. In addition to impairment of lipid synthetic pathway, such as SREBPs, the activation of PPARα by clofibrate was able to up-regulate CPT-1a (first enzyme in FAO) and to reduced the onco-protein levels, such as NF-kB and Erk1/2, in breast cancer cells derived from high metastatic inflammatory tumor specimens [121]. Some evidences indicated PPARα activation as a possible trigger of ineffective tumor metabolism, it was reported that fenofibrate (PPARα agonist) treatment, on cell line and mouse model of oral cancer, supported hexokinase II and VDAC (voltage-dependent anion channel) dissociation, this event destabilized Warburg effect and provided a metabolic switch to OXPHOS, furthermore affected protein expression levels of hexokinase II, PDH and VDAC [125][126][127].…”

Peroxisome Proliferator-Activated Receptor Modulation during Metabolic Diseases and Cancers: Master and Minions

“…In some studies, PPAR α inhibits breast cancer progression, promoting apoptosis of cancer cells through NF κ B signalling. Recently, it was demonstrated that clofibrate presents a high chemosensitivity towards breast cancer cells, in all likelihood through the inhibition of NF- κ B and ERK1/2 activation, which lowers cyclin D1, cyclin A, and cyclin E and induces proapoptotic P21 levels [59]. In contrast, in other studies PPAR α promoted breast cancer progression by releasing leukotriene B4 that activates PPAR α in B cells, inducing the differentiation of B cells and metastasis [60].…”