Peroxisome proliferator–activated receptor α in the human breast cancer cell lines MCF‐7 and MDA‐MB‐231

Suchanek, K. M.; May, Fiona J.; Robinson, J. A.; Lee, Won Jae; Holman, N. A.; Monteith, Gregory R.; Roberts‐Thomson, Sarah J.

doi:10.1002/mc.10061

Cited by 136 publications

(120 citation statements)

References 37 publications

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“…[6][7][8][9][10][11] These data are in agreement with a recent report that PPARa agonists exert pro-inflammatory activities, and with previous findings stating that certain PPARa agonists promote breast cancer cells proliferation. 28,29 PPARa also regulates the expression of lipoprotein receptors and cholesterol transporters, as apolipoprotein E (ApoE), that contains a PPRE sequence on its promoter. 39 Intriguingly, ApoE over-expression has been documented in normal MS 33 and in prostate CSCs.…”

Section: Discussionmentioning

confidence: 99%

“…26 Intriguingly, PPARa, which is activated by the chemical agonist Wy14643 (WY), induces both pro-inflammatory and anti-inflammatory response in target cells. [27][28][29] Here, MS from normal and tumor breast tissues, as well as from tumorigenic MCF7 and non-tumorigenic MCF10 human breast cell lines, were exposed to RARs, RXRs and PPARs agonists. Our data point out that NRs agonists (IIF, RA and PGZ) impair MS formation.…”

Section: Introductionmentioning

confidence: 99%

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Nuclear receptors agonists exert opposing effects on the inflammation dependent survival of breast cancer stem cells

et al. 2012

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Recent literature highlights the importance of pro-inflammatory cytokines in the biology of breast cancer stem cells (CSCs), unraveling differences with respect to their normal counterparts. Expansion of mammospheres (MS) is a valuable tool for the in vitro study of normal and cancer mammary gland stem cells. Here, we expanded MSs from human breast cancer and normal mammary gland tissues, as well from tumorigenic (MCF7) and non-tumorigenic (MCF10) breast cell lines. We observed that agonists for the retinoid X receptor (6-OH-11-O-hydroxyphenanthrene), retinoic acid receptor (all-trans retinoic acid (RA)) and peroxisome proliferator-activated receptor (PPAR)-c (pioglitazone (PGZ)), reduce the survival of MS generated from breast cancer tissues and MCF7 cells, but not from normal mammary gland or MCF10 cells. This phenomenon is paralleled by the hampering of pro-inflammatory Nuclear Factor-jB (NF-jB)/Interleukin-6 (IL6) axis that is hyperactive in breast cancer-derived MS. The hindrance of such pathway associates with the downregulation of MS regulatory genes (SLUG, Notch3, Jagged1) and with the upregulation of the differentiation markers estrogen receptor-a and keratin18. At variance, the PPARa agonist Wy14643 promotes MS formation, upregulating NF-jB/IL6 axis and MS regulatory genes. These data reveal that nuclear receptors agonists (6-OH-11-O-hydroxyphenanthrene, RA, PGZ) reduce the inflammation dependent survival of breast CSCs and that PPARa agonist Wy14643 exerts opposite effects on this phenotype.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Nuclear receptors agonists exert opposing effects on the inflammation dependent survival of breast cancer stem cells

et al. 2012

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“…For all experiments mRNA levels were normalized to 18S rRNA and analyzed relative to the appropriate control (as described in the figure legends). Relative expression levels were calculated using the DDCt method (17).…”

Section: Rna Isolation and Real-time Pcrmentioning

confidence: 99%

ORAI1-Mediated Calcium Influx in Lactation and in Breast Cancer

McAndrew

Grice

Peters

et al. 2011

Molecular Cancer Therapeutics

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The entry of calcium into the mammary epithelial cell from the maternal plasma (i.e., calcium influx mechanisms) during lactation is poorly understood. As alterations in calcium channels and pumps are a key feature of some cancers, including breast cancer, understanding these calcium influx pathways may have significance beyond mammary biology. We show that the store-operated calcium influx protein, Orai1, is increased during lactation whereas the Orai1 activator Stim1, but not Stim2, is downregulated. Stim2 siRNA reduced basal calcium levels in a lactation model. Our results suggest that calcium influx is remodeled in mammary epithelial cells during lactation, with calcium influx increased through Orai1, activated by Stim2. Breast cancer cell lines had increased levels of ORAI1. ORAI1 siRNA in breast cancer cells reduced storeoperated calcium entry and remodeled the calcium influx associated with invasive stimuli. Analysis of microarray data from 295 breast cancers showed that the transcriptional breast cancer subtype with the poorest prognosis (basal) was associated with an altered relationship between the ORAI1 regulators STIM1 and STIM2, and that women with breast cancers with STIM1 high /STIM2 low tumors had a significantly poorer prognosis. Our studies show that during lactation there is a remodeling in the nature of calcium influx and that alteration in the ORAI1 influx pathway may be a feature of some breast cancers, particularly those with the poorest prognosis. Our studies suggest that this pathway may be a novel therapeutic target for breast cancer treatment in these women. Mol Cancer Ther; 10(3); 448-60. Ó2011 AACR.

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“…In contrast, PPAR␥ and PPAR␦ agonists have been extensively studied to evaluate their anticancer effects because of their antiproliferative, proapoptotic, antiapoptotic, and differentiation-promoting activity (4). However, recent studies have revealed the expression of PPAR␣ in tumor cells (5,6), and PPAR␣ ligands suppress the growth of several cancer lines, including colon, breast, endometrial and skin, in vitro (7)(8)(9)(10). PPAR␣ ligands also suppress the metastatic potential of melanoma cells in vitro and in vivo (11,12).…”

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confidence: 99%

PPARα agonist fenofibrate suppresses tumor growth through direct and indirect angiogenesis inhibition

Panigrahy

Kaipainen

Huang

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

244

206

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Angiogenesis and inflammation are central processes through which the tumor microenvironment influences tumor growth. We have demonstrated recently that peroxisome proliferatoractivated receptor (PPAR)␣ deficiency in the host leads to overt inflammation that suppresses angiogenesis via excess production of thrombospondin (TSP)-1 and prevents tumor growth. Hence, we speculated that pharmacologic activation of PPAR␣ would promote tumor growth. Surprisingly, the PPAR␣ agonist fenofibrate potently suppressed primary tumor growth in mice. This effect was not mediated by cancer-cell-autonomous antiproliferative mechanisms but by the inhibition of angiogenesis and inflammation in the host tissue. Although PPAR␣-deficient tumors were still susceptible to fenofibrate, absence of PPAR␣ in the host animal abrogated the potent antitumor effect of fenofibrate. In addition, fenofibrate suppressed endothelial cell proliferation and VEGF production, increased TSP-1 and endostatin, and inhibited corneal neovascularization. Thus, both genetic abrogation of PPAR␣ as well as its activation by ligands cause tumor suppression via overlapping antiangiogenic pathways. These findings reveal the potential utility of the well tolerated PPAR␣ agonists beyond their use as lipid-lowering drugs in anticancer therapy. Our results provide a mechanistic rationale for evaluating the clinical benefits of PPAR␣ agonists in cancer treatment, alone and in combination with other therapies. stroma ͉ inflammation ͉ fibrates ͉ microenvironment P eroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptors comprising three isoforms, PPAR␣, PPAR␦, and PPAR␥, which act as ligand-activated transcriptional factors. PPARs play key roles in energy homeostasis by modulating glucose and lipid metabolism and transport (1). PPAR␣ is also critical in inflammation (2) and is the molecular target of the fibrate class of drugs, such as fenofibrate, which act as agonistic ligands of PPAR␣.Long-term administration of certain PPAR␣ agonists (clofibrate and WY14643) induces hepatocarcinogenesis in rodents but not in humans (3). Consequently, PPAR␣ has not been established as a molecular target for cancer therapy by its agonistic ligands. In contrast, PPAR␥ and PPAR␦ agonists have been extensively studied to evaluate their anticancer effects because of their antiproliferative, proapoptotic, antiapoptotic, and differentiation-promoting activity (4). However, recent studies have revealed the expression of PPAR␣ in tumor cells (5, 6), and PPAR␣ ligands suppress the growth of several cancer lines, including colon, breast, endometrial and skin, in vitro (7-10). PPAR␣ ligands also suppress the metastatic potential of melanoma cells in vitro and in vivo (11,12). Furthermore, PPAR␣ ligands decrease tumor development in murine colon carcinogenesis (7). Clofibric acid inhibits the growth of human ovarian cancer in mice (13). Most recently, the PPAR␣ agonist WY14643 suppresses tumorigenesis in a PPAR␣-dependent manner (14).Together, these data suggest that PPAR...

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Peroxisome proliferator–activated receptor α in the human breast cancer cell lines MCF‐7 and MDA‐MB‐231

Cited by 136 publications

References 37 publications

Nuclear receptors agonists exert opposing effects on the inflammation dependent survival of breast cancer stem cells

Nuclear receptors agonists exert opposing effects on the inflammation dependent survival of breast cancer stem cells

ORAI1-Mediated Calcium Influx in Lactation and in Breast Cancer

PPARα agonist fenofibrate suppresses tumor growth through direct and indirect angiogenesis inhibition

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