PPARs: A Double-Edged Sword in Cancer Therapy?View this Special Issue
Review Article | Open Access
Robert I. Glazer, Hongyan Yuan, Zhihui Xie, Yuzhi Yin, "PPAR and PPAR as Modulators of Neoplasia and Cell Fate", PPAR Research, vol. 2008, Article ID 247379, 8 pages, 2008. https://doi.org/10.1155/2008/247379
PPAR and PPAR as Modulators of Neoplasia and Cell Fate
PPAR and PPAR agonists represent unique classes of drugs that act through their ability to modulate gene transcription associated with intermediary metabolism, differentiation, tumor suppression, and in some instances proliferation and cell adhesion. PPAR agonists are used by millions of people each year to treat type 2 diabetes but may also find additional utility as relatively nontoxic potentiators of chemotherapy. PPAR agonists produce complex actions as shown by their tumor promoting effects in rodents and their cholesterol-lowering action in dyslipidemias. There is now emerging evidence that PPARs regulate tumor suppressor genes and developmental pathways associated with transformation and cell fate determination. This review discusses the role of PPAR and PPAR agonists as modulators of these processes.
PPAR and PPAR are involved in cell cycle regulation, survival and angiogenesis [1–3], and in inflammation through ligand-dependent and independent mechanisms . Several recent reviews have described the role of PPARs in metabolic disease [4–6], cancer treatment [3, 7], and chemoprevention . In addition to their metabolic actions, an emerging area of investigation for PPAR and PPAR agonists is their ability to modulate mammary cell lineage and genes associated with tumor suppressor function and cell fate determination. This suggests that PPAR agonists may play a role in stem/progenitor cell proliferation and differentiation to modify tumor response.
2. PPAR Signaling
The PPAR nuclear receptor subfamily consists of the PPAR, PPAR, and PPAR/ isotypes that regulate a number of metabolic pathways controlling fatty acid -oxidation, glucose utilization, cholesterol transport, energy balance, and adipocyte differentiation [4–6]. PPARs function as heterodimeric partners with RXR, and require high-affinity binding of PPAR ligand to engage transcription . PPARs bind to the DR-1 response element (PPRE) consensus sequence AGG(T/A)CA, which is recognized specifically by the PPAR partner . Like other nuclear receptors, PPARs consist of a putative N-terminal transactivation domain (AF-1), a DNA-binding domain (DBD) containing two zinc fingers, a ligand-binding domain (LBD) containing a large hydrophobic pocket, and a C-terminal ligand-dependent transactivation region (AF-2) .
There is >97% homology at the protein level, 99% homology within the LBD, and minimal functional differences after ligand-dependent activation between human and mouse PPAR, . PPAR is expressed predominantly in white adipose tissue, intestine, endothelial cells, smooth muscle and macrophages , and is the major isotype expressed in the mammary gland, and in primary and metastatic breast cancer and breast cancer cell lines .
Several mutations and polymorphisms have been identified in PPAR, such as Lys319X (truncating) and Gln286Pro, in sporadic colon cancer, which are associated with loss of DNA-binding and ligand-dependent transcription by the PPAR agonist, troglitazone . Similar results were found for PPAR2 polymorphism Pro112Ala , but the polymorphism Ser114Ala resulted in increased transactivation by presumably blocking the inhibitory effect of Ser114 phosphorylation by ERK [15, 16]. However, in a sampling of approximately 400 breast, prostate, colon, and lung tumors and leukemia's, no mutations of the PPAR gene were found, suggesting that if indeed this does occur, it is a very rare event .
In follicular thyroid cancer, the t(2;3)(q13;p25) translocation results in formation of the Pax8-PPAR fusion protein, which is pathoneumonic for the majority of cases of this disease . It acts as a dominant-negative receptor of PPAR [18, 19], and reduces expression of the Ras tumor suppressor, NORE1A , which inhibits ERK activation . PPAR also increases expression of other tumor suppressor genes, such as PTEN  and BRCA1  through their respective PPRE promoter regions, suggesting that the antitumor effects of PPAR agonists may be related to their ability to downregulate multiple tumorigenic signaling pathways. This agrees with the reduction of PTEN and increased nuclear -catenin and ERK activity in the mammary gland and tumors of MMTV-Pax8PPAR mice  (see Figure 1). Since inactivation of BRCA1  and PTEN [26–28] also increases stem cell proliferation, Pax8-PPAR may upregulate specific progenitor cell lineages that are more susceptible to tumorigenesis.
PPARs interact with the coactivators C/EBP, SRC-1, and DRIP205, and in the unliganded state with the corepressor SMRT [19, 29–31], and exhibit similar coactivator/corepressor dynamics as other nuclear receptors, such as estrogen receptor- (ER) . PPAR can interfere with ER transactivation through its binding to the ERE [33, 34], and preferentially partitions with ER for its canonical response elements ; conversely, ER can block PPRE-dependent transcription  (see Figure 1). PPAR also modifies ER signaling by promoting its ubiquitination and degradation  as well as by upregulating CYP19A1 (aromatase) activity [38, 39], which can blunt the activity of aromatase inhibitors used to treat patients with ER+ breast cancer. PPAR agonists block the ER-dependent growth of leiomyoma cells, further suggesting crosstalk between the ER and PPAR signaling pathways. PPAR and ER pathways have opposite effects on PI3K/AKT signaling that may also account for the inhibitory action of PPAR ligands on ER-dependent breast cancer cells  (see Figure 1). These findings imply that PPAR antagonism should upregulate ER expression in responsive tissues, which is precisely the phenotype observed in mammary tumors induced in transgenic mice expressing Pax8PPAR .
Studies using transgenic and knockout mouse models of PPAR have led to disparate conclusions regarding the role of PPAR in tumorigenesis. Mice expressing constitutively active VP16-PPAR in the mammary gland did not exhibit a tumorigenic phenotype but accelerated tumorigenesis when crossed with MMTV-polyoma middle-T antigen mice , intimating that the unliganded receptor may have interfered with tumor suppressor transactivation by endogenous PPAR through corepressor recruitment. Alternatively, the VP16 fusion protein is known to induce many genes that are not indicative of PPAR activation . In the probasin-SV40 T-antigen prostate tumor model, tumorigenesis was unaffected by a PPAR null background , indicating that oncogenic signaling was already maximally activated. However, in the ApcMin mouse colon tumor model, “glitazone” PPAR agonists increased the number of colon, but not small intestine polyps [43, 44], as well as colon adenomas . Since the small intestine, and not the colon, is the predominant site of neoplasia in this mouse model, the significance of this observation is unclear. It should also be stressed that PPAR agonists did not induce malignant changes in wild type mice, indicating their lack of carcinogenicity. Contrary to these results, PPAR haploinsufficiency produced a greater rate and number of colon tumors following azoxymethane-induced carcinogenesis , implying that PPAR acts as a tumor suppressor rather than as an oncogene. APC+/1638N mice heterozygous for PPAR did not exhibit changes in polyp formation . This result indicates that the induction of -catenin in the colonic crypt cells of PPAR haplosufficient mice, a protumorigenic factor that is constitutively activated in APC mice, is the target of tumor suppression in wild-type mice . A tumor suppressor role for PPAR is also supported by the inhibitory effect of PPAR agonists on colon tumor growth [48, 49], and mammary carcinogenesis [50–52]. This effect may be mediated in breast tumors through induction of apoptosis due to reduction of Bcl-2 , and in pancreatic and liver tumors through a reduction of cyclin D1 and HB-EGF  and an increase of p27Kip1 [55–57]. PPAR agonists may also find utility as modifiers of the response to chemotherapy. CS-7017, a potent thiazolidinedione agonist, synergized with paclitaxel to inhibit the growth of anaplastic thyroid tumors through induction of p21Cip1 . Notwithstanding possible “off-target” effects [59, 60], most studies indicate that PPAR agonists as a class have antitumor activity, and thus may have efficacy as a relatively nontoxic adjunct to chemotherapy and possibly to radiation therapy through their ability to act as “tumor suppressor enhancers.”
3. PPAR Signaling
As with PPAR, PPAR is involved in adipocyte differentiation by promoting clonal expansion of preadipocyte progenitor cells , possibly through activation of PPAR expression . The PPAR agonist GW501516 has been tested clinically as a cholesterol lowering drug in dyslipidemic patients, but the results have been mixed . In animal models, homozygous disruption of PPAR resulted in a runted phenotype  and in 90% embryonic lethality with runted survivors , indicating its importance in embryonic development. PPAR null macrophages exhibited loss of the dominant inhibitory effect by unliganded PPAR , which was previously identified by its ability to block PPAR and PPAR transactivation through corepressor recruitment [60, 66, 67]. In breast cancer cells, PPAR expression was greater in ER− MDA-MB-231 breast cancer cells than in ER+ MCF-7 cells , also suggesting a correlation with a more aggressive form of this disease. Indeed, tissue microarray analysis of invasive breast cancers indicated that PPAR is strongly expressed (see Figure 2, “+3”) in 52% of 164 samples, and thus may have value as a prognostic marker and therapeutic target. There are no examples of the development of PPARantagonists as anticancer therapeutics.
GW501516 accelerated the onset of tumor formation during mammary carcinogenesis, in contrast to the delay of tumor formation by PPAR agonist GW7845 . PPAR expression increased in K-Ras-transformed intestinal epithelial cells  and PDGF-stimulated vascular smooth muscle cells . Similar findings were reported for conditional expression of PPAR, where GW501516 increased proliferation of hormone-dependent breast and prostate cancer cells and endothelial cells, and increased expression of genes associated with proliferation and angiogenesis . PPAR can suppress the antiproliferative effects of PPAR and PPAR  and directly associate with PDK1  to affect its localization and activation [72, 73], which implicate it as a protumorigenic factor, and therefore raise a caution for the general use of this class of agonists .
Colon cancer presents an interesting model to exam the role of PPAR in tumorigenesis since ApcMin mice exhibit constitutive activation of -catenin/TCF signaling, the pathway believed to activate PPAR . PPAR is highly expressed in colorectal cancer cells , and somatic cell knockout of PPAR reduced tumorigenicity in nude mice . Crossing PPAR null or heterozygous mice with ApcMin mice showed a gene dosage dependent reduction in large intestinal polyps , and treatment of ApcMin mice with GW501516 produced an increase in both polyp number and size , all suggesting that PPAR is protumorigenic. However, a study using a different targeting scheme to delete PPAR reported no change in polyp number or size in the small intestine of ApcMin mice, and a greater number but not size of carcinogen-induced colon tumors in mice with this background . Since the PPAR knockout mice generated by Barak contained a deletion of exon 4 encoding the hinge region , whereas, that generated by Peters et al.  contained a deletion of the last exon encoding the AF2 domain, it is possible that the truncated PPAR may not be as susceptible to corepression as the wild-type receptor. This would explain why their results [79, 80] differ from studies showing that keratinocytes from mice heterozygous or null for PPAR exhibit less proliferation  and those in ApcMin mice in a PPAR null background exhibit increased tumorigenesis . From a mechanistic standpoint, PPAR is activated in colon cancer cells by prostacyclin (PGI2)  and inhibited by the NSAID indomethacin , suggesting that its tumor promoting action is related to inflammation, a condition that increases the risk of colon cancer . NSAIDs downregulate PPAR and reduce eicosanoid-mediated inflammation , and induce apoptosis in colon cancer cells , in contradistinction to the anti-inflammatory effects elicited by PPAR agonists in colitis . Increased expression of PPAR in tumors may also inhibit PPAR transcription [60, 66, 67], and reduce its tumor suppressor activity, as mentioned above in colon tumorigenesis. In addition, the tumor promoting effects of PPAR in the mammary gland relate to activation of -catenin/TCF signaling [76, 87] (see Figure 3), which is increased in cells transformed by PDK1 [88, 89]. PDK1 is a key regulator downstream of PI3K that is increased by PPAR in keratinocytes [72, 73]. Mammary tumors formed after administration of GW501516 exhibit an association between PDK1 and PPAR , which further suggests that PPAR may function as an integrator of proliferative and prosurvival pathways downstream of oncogenic signaling and inflammation [90, 91], which are likely to account for its tumor promoting effects.
PPARs and stem cells
There is evidence that PPARs can modulate stem and progenitor cell expansion and the differentiated or malignant phenotype. PPAR agonists enhance adipocyte differentiation [5, 6], and its ability to upregulate this process has a negative effect on osteoblast proliferation and bone development from mesenchymal stem cells . To counteract this inhibitory effect in bone stem cells, PPAR must be transrepressed through corepressor recruitment by the NFκB and Wnt-5a pathways . It is therefore likely that PPARs influence the fate of other stem and progenitor cell populations in normal and malignant tissues. PPAR agonists have been used as chemopreventive agents  to delay mammary carcinogenesis [51, 52]. One aspect to their chemopreventive action may relate to their influence on specific cell lineages, as in mesenchymal stem cells. Carcinogens target stem cells rather than terminally differentiated cells [95, 96] as well as hormone-responsive lineages  during mammary carcinogenesis. Carcinogenesis is markedly attenuated in PR-null mice, and is accelerated by progestin treatment of wild-type mice [52, 99–101], where progestins are believed to stimulate the proliferation of stem or early progenitor cells that are intrinsically more susceptible to tumor initiation . The ability of PPAR and PPAR agonists to modulate distinct cell lineages during mammary tumorigenesis  also suggests that they modulate a complex transcriptional network linked to cell fate [3, 5]. PPAR agonist GW501516 promoted the development of adenosquamous carcinomas with high expression of the stem cell markers CK19 and Notch1, as well as Proliferin, a growth factor that mediates many of the effects of the stem cell marker, Musashi1, in mammary cells . PPAR is expressed in the crypt cells of the small intestine and negatively regulates Hedgehog signaling to block differentiation , a process that would be expected to promote transformation. PPAR expression lies downstream of -catenin/TCF , and activation of this pathway increases expression of luminal epithelial and myoepithelial cells  as well as mammary tumor cells expressing the stem cell marker Sca-1 . Thus, PPAR activation may promote expansion of a less differentiated lineage or stem cells that is intrinsically more susceptible to tumorigenesis. The association of Wnt activation with stem cell expansion, activation of -catenin/TCF signaling by PDK1, the identification of PPAR as a -catenin/TCF target gene and PDK1 as a PPAR responsive gene, as well as the modulation of Sca-1+ stem/progenitor cells by the Wnt pathway, all suggest a common mechanism for the tumor promoting action of PPAR agonists that may involve stem and progenitor cell proliferation (see Figure 3). This mechanism also suggests that the development of PPAR antagonists may have utility as cancer therapeutics
PPAR increases expression of the PPRE-dependent tumor suppressor genes PTEN  and BRCA1 , suggesting that their chemopreventive effects may be related to the ability of these suppressor genes to promote a more differentiated lineage. On the contrary, inactivation of BRCA1  and PTEN [26–28] should increase stem cell proliferation, which is precisely the case. This effect is similar to what has been described for PPAR agonists in preventing differentiation and increasing stem cell abundance, and would be expected to complement their tumor promoting activity. Although studies examining the influence of PPARs on cell fate determination are just in their infancy, many of the studies cited imply that their opposing roles in tumorigenesis may be related to their ability to control the programming of specific cell lineages.
The ability of PPAR agonists to modulate the transcriptional activity of this class of nuclear receptors has generated an enormous interest in being able to pharmacologically manipulate entire sets of genes that can modulate metabolism, inflammation, transformation, differentiation and thus, tumorigenesis. Both genetic and pharmacological approaches to determining the function of PPAR and PPAR have yielded some inconsistencies, but that may be explained by the inherent deficiency of either approach. Gene targeting resulting in a truncated gene product may not necessarily recapitulate gene inactivation, and homozygous loss of gene expression can affect the developmental programming of various tissues that can impact directly or indirectly on the outcome of tumorigenesis in a particular organ. By the same token, pharmacological approaches are fraught with the structure-specific and class-specific side effects inherent in most drugs, which may be unrelated to their specific actions on the drug target. Nevertheless, the majority of studies in this field implicate PPAR activation as an antitumorigenic and prodifferentiation factor, in contrast to the protumorigenic and less differentiated phenotype resulting from PPAR activation. Although the latter characteristic will likely preclude the clinical development of PPAR agonists, it will be interesting to see the outcome of current clinical trials utilizing PPAR agonists as antitumor and chemotherapy modulating therapy.
The authors acknowledge support from the National Institutes of Health, Sankyo Co., and The Charlotte Geyer Foundation.
- J. Auwerx, “Nuclear receptors I. PPAR in the gastrointestinal tract: gain or pain?” American Journal of Physiology: Gastrointestinal and Liver Physiology, vol. 282, no. 4, pp. G581–G585, 2002.
- H. P. Koeffler, “Peroxisome proliferator-activated receptor and cancers,” Clinical Cancer Research, vol. 9, no. 1, pp. 1–9, 2003.
- L. Michalik, B. Desvergne, and W. Wahli, “Peroxisome-proliferator-activated receptors and cancers: complex stories,” Nature Reviews Cancer, vol. 4, no. 1, pp. 61–70, 2004.
- J. P. Berger, T. E. Akiyama, and P. T. Meinke, “PPARs: therapeutic targets for metabolic disease,” Trends in Pharmacological Sciences, vol. 26, no. 5, pp. 244–251, 2005.
- R. M. Evans, G. D. Barish, and Y.-X. Wang, “PPARs and the complex journey to obesity,” Nature Medicine, vol. 10, no. 4, pp. 355–361, 2004.
- M. Lehrke and M. A. Lazar, “The many faces of PPAR,” Cell, vol. 123, no. 6, pp. 993–999, 2005.
- C. Grommes, G. E. Landreth, and M. T. Heneka, “Antineoplastic effects of peroxisome proliferator-activated receptor agonists,” The Lancet Oncology, vol. 5, no. 7, pp. 419–429, 2004.
- L. Kopelovich, J. R. Fay, R. I. Glazer, and J. A. Crowell, “Peroxisome proliferator-activated receptor modulators as potential chemopreventive agents,” Molecular Cancer Therapeutics, vol. 1, no. 5, pp. 357–363, 2002.
- J. Berger and J. A. Wagner, “Physiological and therapeutic roles of peroxisome proliferator-activated receptors,” Diabetes Technology and Therapeutics, vol. 4, no. 2, pp. 163–174, 2002.
- J. M. Olefsky and A. R. Saltiel, “PPAR and the treatment of insulin resistance,” Trends in Endocrinology and Metabolism, vol. 11, no. 9, pp. 362–368, 2000.
- T. M. Willson, P. J. Brown, D. D. Sternbach, and B. R. Henke, “The PPARs: from orphan receptors to drug discovery,” Journal of Medicinal Chemistry, vol. 43, no. 4, pp. 527–550, 2000.
- C. Knouff and J. Auwerx, “Peroxisome proliferator-activated receptor- calls for activation in moderation: lessons from genetics and pharmacology,” Endocrine Reviews, vol. 25, no. 6, pp. 899–918, 2004.
- P. Sarraf, E. Mueller, W. M. Smith et al., “Loss-of-function mutations in PPAR associated with human colon cancer,” Molecular Cell, vol. 3, no. 6, pp. 799–804, 1999.
- S. S. Deeb, L. Fajas, M. Nemoto et al., “A Pro12Ala substitution in PPAR2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity,” Nature Genetics, vol. 20, no. 3, pp. 284–287, 1998.
- M. Ristow, D. Müller-Wieland, A. Pfeiffer, W. Krone, and C. R. Kahn, “Obesity associated with a mutation in a genetic regulator of adipocyte differentiation,” The New England Journal of Medicine, vol. 339, no. 14, pp. 953–959, 1998.
- D. Shao and M. A. Lazar, “Peroxisome proliferator activated receptor , CCAAT/enhancer-binding protein , and cell cycle status regulate the commitment to adipocyte differentiation,” Journal of Biological Chemistry, vol. 272, no. 34, pp. 21473–21478, 1997.
- T. Ikezoe, C. W. Miller, S. Kawano et al., “Mutational analysis of the peroxisome proliferator-activated receptor in human malignancies,” Cancer Research, vol. 61, no. 13, pp. 5307–5310, 2001.
- T. G. Kroll, P. Sarraf, L. Pecciarini et al., “PAX8-PPAR1 fusion in oncogene human thyroid carcinoma,” Science, vol. 289, no. 5483, pp. 1357–1360, 2000.
- Y. Yin, H. Yuan, C. Wang et al., “3-phosphoinositide-dependent protein kinase-1 activates the peroxisome proliferator-activated receptor- and promotes adipocyte differentiation,” Molecular Endocrinology, vol. 20, no. 2, pp. 268–278, 2006.
- T. Foukakis, A. Y. M. Au, G. Wallin et al., “The Ras effector NORE1A is suppressed in follicular thyroid carcinomas with a PAX8-PPAR fusion,” The Journal of Clinical Endocrinology & Metabolism, vol. 91, no. 3, pp. 1143–1149, 2006.
- A. Moshnikova, J. Frye, J. W. Shay, J. D. Minna, and A. V. Khokhlatchev, “The growth and tumor suppressor NORE1A is a cytoskeletal protein that suppresses growth by inhibition of the ERK pathway,” Journal of Biological Chemistry, vol. 281, no. 12, pp. 8143–8152, 2006.
- L. Patel, I. Pass, P. Coxon, C. P. Downes, S. A. Smith, and C. H. Macphee, “Tumor suppressor and anti-inflammatory actions of PPAR agonists are mediated via upregulation of PTEN,” Current Biology, vol. 11, no. 10, pp. 764–768, 2001.
- M. Pignatelli, C. Cocca, A. Santos, and A. Perez-Castillo, “Enhancement of BRCA1 gene expression by the peroxisome proliferator-activated receptor in the MCF-7 breast cancer cell line,” Oncogene, vol. 22, no. 35, pp. 5446–5450, 2003.
- Y. Yin, H. Yuan, S. Mueller, L. Kopelovich, and R. I. Glazer, “Peroxisome proliferator-activated receptor is a regulator of mammary stem and progenitor cell self-renewal and estrogen-dependent tumor specification,” in Proceedings of the American Association for Cancer Research, Los Angeles, Calif, USA, April 2007.
- S. Liu, C. Ginestier, E. Charafe-Jauffret et al., “BRCA1 regulates human mammary stem/progenitor cell fate,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 5, pp. 1680–1685, 2008.
- A. D. Cristofano, B. Pesce, C. Cordon-Cardo, and P. P. Pandolfi, “Pten is essential for embryonic development and tumour suppression,” Nature Genetics, vol. 19, no. 4, pp. 348–355, 1998.
- S. Wang, A. J. Garcia, M. Wu, D. A. Lawson, O. N. Witte, and H. Wu, “Pten deletion leads to the expansion of a prostatic stem/progenitor cell subpopulation and tumor initiation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 5, pp. 1480–1485, 2006.
- M. Groszer, R. Erickson, D. D. Scripture-Adams et al., “Negative regulation of neural stem/progenitor cell proliferation by the Pten tumor suppressor gene in vivo,” Science, vol. 294, no. 5549, pp. 2186–2189, 2001.
- J. DiRenzo, M. Söderström, R. Kurokawa et al., “Peroxisome proliferator-activated receptors and retinoic acid receptors differentially control the interactions of retinoid X receptor heterodimers with ligands, coactivators, and corepressors,” Molecular and Cellular Biology, vol. 17, no. 4, pp. 2166–2176, 1997.
- R. M. Lavinsky, K. Jepsen, T. Heinzel et al., “Diverse signaling pathways modulate nuclear receptor recruitment of N-CoR and SMRT complexes,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 6, pp. 2920–2925, 1998.
- R. T. Nolte, G. B. Wisely, S. Westin et al., “Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-,” Nature, vol. 395, no. 6698, pp. 137–143, 1998.
- Y. Shang, X. Hu, J. DiRenzo, M. A. Lazar, and M. Brown, “Cofactor dynamics and sufficiency in estrogen receptor-regulated transcription,” Cell, vol. 103, no. 6, pp. 843–852, 2000.
- K. D. Houston, J. A. Copland, R. R. Broaddus, M. M. Gottardis, S. M. Fischer, and C. L. Walker, “Inhibition of proliferation and estrogen receptor signaling by peroxisome proliferator-activated receptor ligands in uterine leiomyoma,” Cancer Research, vol. 63, no. 6, pp. 1221–1227, 2003.
- H. Keller, F. Givel, M. Perroud, and W. Wahli, “Signaling cross-talk between peroxisome proliferator-activated receptor/retinoid X receptor and estrogen receptor through estrogen response elements,” Molecular Endocrinology, vol. 9, no. 7, pp. 794–804, 1995.
- Y. Liu, H. Gao, T. T. Marstrand et al., “The genome landscape of ER- and ER-binding DNA regions,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 7, pp. 2604–2609, 2008.
- D. Bonofiglio, S. Gabriele, S. Aquila et al., “Estrogen receptor binds to peroxisome proliferator-activated receptor response element and negatively interferes with peroxisome proliferator-activated receptor signaling in breast cancer cells,” Clinical Cancer Research, vol. 11, no. 17, pp. 6139–6147, 2005.
- C. Qin, R. Burghardt, R. Smith, M. Wormke, J. Stewart, and S. Safe, “Peroxisome proliferator-activated receptor agonists induce proteasome-dependent degradation of cyclin D1 and estrogen receptor in MCF-7 breast cancer cells,” Cancer Research, vol. 63, no. 5, pp. 958–964, 2003.
- T. Yanase, Y.-M. Mu, Y. Nishi et al., “Regulation of aromatase by nuclear receptors,” Journal of Steroid Biochemistry and Molecular Biology, vol. 79, no. 1–5, pp. 187–192, 2001.
- W. Fan, T. Yanase, H. Morinaga et al., “Activation of peroxisome proliferator-activated receptor- and retinoid X receptor inhibits aromatase transcription via nuclear factor-B,” Endocrinology, vol. 146, no. 1, pp. 85–92, 2005.
- E. Saez, J. Rosenfeld, A. Livolsi et al., “PPAR signaling exacerbates mammary gland tumor development,” Genes & Development, vol. 18, no. 5, pp. 528–540, 2004.
- Y. Li and M. A. Lazar, “Differential gene regulation by PPAR agonist and constitutively active PPAR2,” Molecular Endocrinology, vol. 16, no. 5, pp. 1040–1048, 2002.
- E. Saez, P. Olson, and R. M. Evans, “Genetic deficiency in Pparg does not alter development of experimental prostate cancer,” Nature Medicine, vol. 9, no. 10, pp. 1265–1266, 2003.
- A.-M. Lefebvre, I. Chen, P. Desreumaux et al., “Activation of the peroxisome proliferator-activated receptor promotes the development of colon tumors in C57BL/6J-/+ mice,” Nature Medicine, vol. 4, no. 9, pp. 1053–1057, 1998.
- E. Saez, P. Tontonoz, M. C. Nelson et al., “Activators of the nuclear receptor PPAR enhance colon polyp formation,” Nature Medicine, vol. 4, no. 9, pp. 1058–1061, 1998.
- M. V. Pino, M. F. Kelley, and Z. Jayyosi, “Promotion of colon tumors in C57BL/6J-/+ mice by thiazolidinedione PPAR agonists and a structurally unrelated PPAR agonist,” Toxicologic Pathology, vol. 32, no. 1, pp. 58–63, 2004.
- G. D. Girnun, W. M. Smith, S. Drori et al., “APC-dependent suppression of colon carcinogenesis by PPAR,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 21, pp. 13771–13776, 2002.
- D. Lu, H. B. Cottam, M. Corr, and D. A. Carson, “Repression of -catenin function in malignant cells by nonsteroidal antiinflammatory drugs,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 51, pp. 18567–18571, 2005.
- J. A. Brockman, R. A. Gupta, and R. N. Dubois, “Activation of PPAR leads to inhibition of anchorage-independent growth of human colorectal cancer cells,” Gastroenterology, vol. 115, no. 5, pp. 1049–1055, 1998.
- P. Sarraf, E. Mueller, D. Jones et al., “Differentiation and reversal of malignant changes in colon cancer through PPAR,” Nature Medicine, vol. 4, no. 9, pp. 1046–1052, 1998.
- G. M. Pighetti, W. Novosad, C. Nicholson et al., “Therapeutic treatment of DMBA-induced mammary tumors with PPAR ligands,” Anticancer Research, vol. 21, no. 2A, pp. 825–829, 2001.
- N. Suh, Y. Wang, C. R. Williams et al., “A new ligand for the peroxisome proliferator-activated receptor- (PPAR-), GW7845, inhibits rat mammary carcinogenesis,” Cancer Research, vol. 59, no. 22, pp. 5671–5673, 1999.
- Y. Yin, R. G. Russell, L. E. Dettin et al., “Peroxisome proliferator-activated receptor and agonists differentially alter tumor differentiation and progression during mammary carcinogenesis,” Cancer Research, vol. 65, no. 9, pp. 3950–3957, 2005.
- E. Elstner, C. Müller, K. Koshizuka et al., “Ligands for peroxisome proliferator-activated receptor and retinoic acid receptor inhibit growth and induce apoptosis of human breast cancer cells in vitro and in BNX mice,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 15, pp. 8806–8811, 1998.
- S. Kitamura, Y. Miyazaki, S. Hiraoka et al., “PPAR agonists inhibit cell growth and suppress the expression of cyclin D1 and EGF-like growth factors in ras-transformed rat intestinal epithelial cells,” International Journal of Cancer, vol. 94, no. 3, pp. 335–342, 2001.
- W. Motomura, T. Okumura, N. Takahashi, T. Obara, and Y. Kohgo, “Activation of peroxisome proliferator-activated receptor by troglitazone inhibits cell growth through the increase of in human pancreatic carcinoma cells,” Cancer Research, vol. 60, no. 19, pp. 5558–5564, 2000.
- A. Itami, G. Watanabe, Y. Shimada et al., “Ligands for peroxisome proliferator-activated receptor inhibit growth of pancreatic cancers both in vitro and in vivo,” International Journal of Cancer, vol. 94, no. 3, pp. 370–376, 2001.
- H. Koga, S. Sakisaka, M. Harada et al., “Involvement of , , and in troglitazone-induced cell-cycle arrest in human hepatoma cell lines,” Hepatology, vol. 33, no. 5, pp. 1087–1097, 2001.
- J. A. Copland, L. A. Marlow, S. Kurakata et al., “Novel high-affinity PPAR agonist alone and in combination with paclitaxel inhibits human anaplastic thyroid carcinoma tumor growth via ,” Oncogene, vol. 25, no. 16, pp. 2304–2317, 2006.
- C.-W. Shiau, C.-C. Yang, S. K. Kulp et al., “Thiazolidenediones mediate apoptosis in prostate cancer cells in part through inhibition of Bcl-xL/Bcl-2 functions independently of PPAR,” Cancer Research, vol. 65, no. 4, pp. 1561–1569, 2005.
- C.-H. Lee, A. Chawla, N. Urbiztondo, D. Liao, W. A. Boisvert, and R. M. Evans, “Transcriptional repression of atherogenic inflammation: modulation by PPAR,” Science, vol. 302, no. 5644, pp. 453–457, 2003.
- J. B. Hansen, H. Zhang, T. H. Rasmussen, R. K. Petersen, E. N. Flindt, and K. Kristiansen, “Peroxisome proliferator-activated receptor (PPAR)-mediated regulation of preadipocyte proliferation and gene expression is dependent on cAMP signaling,” Journal of Biological Chemistry, vol. 276, no. 5, pp. 3175–3182, 2001.
- D. Holst, S. Luquet, K. Kristiansen, and P. A. Grimaldi, “Roles of peroxisome proliferator-activated receptors delta and gamma in myoblast transdifferentiation,” Experimental Cell Research, vol. 288, no. 1, pp. 168–176, 2003.
- P. Pelton, “GW-501516 GlaxoSmithKline/ligand,” Current Opinion in Investigational Drugs, vol. 7, no. 4, pp. 360–370, 2006.
- J. M. Peters, S. S. T. Lee, W. Li et al., “Growths, adipose, brain, and skin alterations resulting from targeted disruption of the mouse peroxisome proliferator-activated receptor (),” Molecular and Cellular Biology, vol. 20, no. 14, pp. 5119–5128, 2000.
- Y. Barak, D. Liao, W. He et al., “Effects of peroxisome proliferator-activated receptor on placentation, adiposity, and colorectal cancer,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 1, pp. 303–308, 2002.
- L. Jow and R. Mukherjee, “The human peroxisome proliferator-activated receptor (PPAR) subtype NUC1 represses the activation of hPPAR and thyroid hormone receptors,” Journal of Biological Chemistry, vol. 270, no. 8, pp. 3836–3840, 1995.
- Y. Shi, M. Hon, and R. M. Evans, “The peroxisome proliferator-activated receptor , an integrator of transcriptional repression and nuclear receptor signaling,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 5, pp. 2613–2618, 2002.
- K. M. Suchanek, F. J. May, W. J. Lee, N. A. Holman, and S. J. Roberts-Thomson, “Peroxisome proliferator-activated receptor expression in human breast epithelial cell lines of tumorigenic and non-tumorigenic origin,” International Journal of Biochemistry and Cell Biology, vol. 34, no. 9, pp. 1051–1058, 2002.
- J. Shao, H. Sheng, and R. N. DuBois, “Peroxisome proliferator-activated receptors modulate K-Ras-mediated transformation of intestinal epithelial cells,” Cancer Research, vol. 62, no. 11, pp. 3282–3288, 2002.
- J. Zhang, M. Fu, X. Zhu et al., “Peroxisome proliferator-activated receptor is up-regulated during vascular lesion formation and promotes post-confluent cell proliferation in vascular smooth muscle cells,” Journal of Biological Chemistry, vol. 277, no. 13, pp. 11505–11512, 2002.
- R. L. Stephen, M. C. U. Gustafsson, M. Jarvis et al., “Activation of peroxisome proliferator-activated receptor stimulates the proliferation of human breast and prostate cancer cell lines,” Cancer Research, vol. 64, no. 9, pp. 3162–3170, 2004.
- N. Di-Poï, N. S. Tan, L. Michalik, W. Wahli, and B. Desvergne, “Antiapoptotic role of PPAR in keratinocytes via transcriptional control of the Akt1 signaling pathway,” Molecular Cell, vol. 10, no. 4, pp. 721–733, 2002.
- N. Di-Poï, L. Michalik, N. S. Tan, B. Desvergne, and W. Wahli, “The anti-apoptotic role of PPAR contributes to efficient skin wound healing,” Journal of Steroid Biochemistry and Molecular Biology, vol. 85, no. 2–5, pp. 257–265, 2003.
- M. H. Fenner and E. Elstner, “Peroxisome proliferator-activated receptor- ligands for the treatment of breast cancer,” Expert Opinion on Investigational Drugs, vol. 14, no. 6, pp. 557–568, 2005.
- T.-C. He, T. A. Chan, B. Vogelstein, and K. W. Kinzler, “PPAR is an APC-regulated target of nonsteroidal anti-inflammatory drugs,” Cell, vol. 99, no. 3, pp. 335–345, 1999.
- B. H. Park, B. Vogelstein, and K. W. Kinzler, “Genetic disruption of PPAR decreases the tumorigenicity of human colon cancer cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 5, pp. 2598–2603, 2001.
- R. A. Gupta, D. Wang, S. Katkuri, H. Wang, S. K. Dey, and R. N. DuBois, “Activation of nuclear hormone receptor peroxisome proliferator-activated receptor- accelerates intestinal adenoma growth,” Nature Medicine, vol. 10, no. 3, pp. 245–247, 2004.
- F. S. Harman, C. J. Nicol, H. E. Marin, J. M. Ward, F. J. Gonzalez, and J. M. Peters, “Peroxisome proliferator-activated receptor- attenuates colon carcinogenesis,” Nature Medicine, vol. 10, no. 5, pp. 481–483, 2004.
- D. J. Kim, I. A. Murray, A. M. Burns, F. J. Gonzalez, G. H. Perdew, and J. M. Peters, “Peroxisome proliferator-activated receptor-/ inhibits epidermal cell proliferation by down-regulation of kinase activity,” Journal of Biological Chemistry, vol. 280, no. 10, pp. 9519–9527, 2005.
- H. E. Hollingshead, M. G. Borland, A. N. Billin, T. M. Willson, F. J. Gonzalez, and J. M. Peters, “Ligand activation of peroxisome proliferator-activated receptor-/ (PPAR/) and inhibition of cyclooxygenase 2 (COX2) attenuate colon carcinogenesis through independent signaling mechanisms,” Carcinogenesis, vol. 29, no. 1, pp. 169–176, 2008.
- L. Michalik, B. Desvergne, N. S. Tan et al., “Impaired skin wound healing in peroxisome proliferator-activated receptor (PPAR) and PPAR mutant mice,” Journal of Cell Biology, vol. 154, no. 4, pp. 799–814, 2001.
- R. A. Gupta, J. Tan, W. F. Krause et al., “Prostacyclin-mediated activation of peroxisome proliferator-activated receptor in colorectal cancer,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 24, pp. 13275–13280, 2000.
- W. Strober, I. Fuss, and P. Mannon, “The fundamental basis of inflammatory bowel disease,” Journal of Clinical Investigation, vol. 117, no. 3, pp. 514–521, 2007.
- I. Shureiqi, D. Chen, R. Lotan et al., “15-lipoxygenase-1 mediates nonsteroidal anti-inflammatory drug-induced apoptosis independently of cyclooxygenase-2 in colon cancer cells,” Cancer Research, vol. 60, no. 24, pp. 6846–6850, 2000.
- I. Shureiqi, W. Jiang, X. Zuo et al., “The 15-lipoxygenase-1 product 13-S-hydroxyoctadecadienoic acid down-regulates PPAR- to induce apoptosis in colorectal cancer cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 17, pp. 9968–9973, 2003.
- C. G. Su, X. Wen, S. T. Bailey et al., “A novel therapy for colitis utilizing PPAR- ligands to inhibit the epithelial inflammatory response,” Journal of Clinical Investigation, vol. 104, no. 4, pp. 383–389, 1999.
- T.-C. He, A. B. Sparks, C. Rago et al., “Identification of c-MYC as a target of the APC pathway,” Science, vol. 281, no. 5382, pp. 1509–1512, 1998.
- Z. Xie, X. Zeng, T. Waldman, and R. I. Glazer, “Transformation of mammary epithelial cells by 3-phosphoinositide-dependent protein kinase-1 activates -catenin and c-Myc, and down-regulates caveolin-1,” Cancer Research, vol. 63, no. 17, pp. 5370–5375, 2003.
- X. Zeng, H. Xu, and R. I. Glazer, “Transformation of mammary epithelial cells by 3-phosphoinositide-dependent protein kinase-1 (PDK1) is associated with the induction of protein kinase C,” Cancer Research, vol. 62, no. 12, pp. 3538–3543, 2002.
- H. Lim, R. A. Gupta, W.-G. Ma et al., “Cyclo-oxygenase-2-derived prostacyclin mediates embryo implantation in the mouse via PPAR,” Genes & Development, vol. 13, no. 12, pp. 1561–1574, 1999.
- B. M. Forman, J. Chen, and R. M. Evans, “Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors and ,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 9, pp. 4312–4317, 1997.
- X. Ma, K.-W. Ling, and E. Dzierzak, “Cloning of the Ly-6A (Sca-1) gene locus and identification of a distal fragment responsible for high-level -interferon-induced expression in vitro,” British Journal of Haematology, vol. 114, no. 3, pp. 724–730, 2001.
- E. J. Moerman, K. Teng, D. A. Lipschitz, and B. Lecka-Czernik, “Aging activates adipogenic and suppresses osteogenic programs in mesenchymal marrow stroma/stem cells: the role of PPAR-2 transcription factor and TGF-/BMP signaling pathways,” Aging Cell, vol. 3, no. 6, pp. 379–389, 2004.
- I. Takada, M. Suzawa, K. Matsumoto, and S. Kato, “Suppression of PPAR transactivation switches cell fate of bone marrow stem cells from adipocytes into osteoblasts,” Annals of the New York Academy of Sciences, vol. 1116, pp. 182–195, 2007.
- J. Russo and I. H. Russo, “Influence of differentiation and cell kinetics on the susceptibility of the rat mammary gland to carcinogenesis,” Cancer Research, vol. 40, no. 8, part 1, pp. 2677–2687, 1980.
- L. Sivaraman, J. Gay, S. G. Hilsenbeck et al., “Effect of selective ablation of proliferating mammary epithelial cells on MNU induced rat mammary tumorigenesis,” Breast Cancer Research and Treatment, vol. 73, no. 1, pp. 75–83, 2002.
- D. Medina, F. S. Kittrell, A. Shepard, A. Contreras, J. M. Rosen, and J. Lydon, “Hormone dependence in premalignant mammary progression,” Cancer Research, vol. 63, no. 5, pp. 1067–1072, 2003.
- J. P. Lydon, G. Ge, F. S. Kittrell, D. Medina, and B. W. O'Malley, “Murine mammary gland carcinogenesis is critically dependent on progesterone receptor function,” Cancer Research, vol. 59, no. 17, pp. 4276–4284, 1999.
- C. M. Aldaz, Q. Y. Liao, M. LaBate, and D. A. Johnston, “Medroxyprogesterone acetate accelerates the development and increases the incidence of mouse mammary tumors induced by dimethylbenzanthracene,” Carcinogenesis, vol. 17, no. 9, pp. 2069–2072, 1996.
- P. Pazos, C. Lanari, R. Meiss, E. H. Charreau, and C. D. Pasqualini, “Mammary carcinogenesis induced by N-methyl-N-nitrosourea (MNU) and medroxyprogesterone acetate (MPA) in BALB/c mice,” Breast Cancer Research and Treatment, vol. 20, no. 2, pp. 133–138, 1992.
- Y. Yin, R. Bai, R. G. Russell et al., “Characterization of medroxyprogesterone and DMBA-induced multilineage mammary tumors by gene expression profiling,” Molecular Carcinogenesis, vol. 44, no. 1, pp. 42–50, 2005.
- S. Naylor, M. J. Smalley, D. Robertson, B. A. Gusterson, P. A. W. Edwards, and T. C. Dale, “Retroviral expression of Wnt-1 and Wnt-7b produces different effects in mouse mammary epithelium,” Journal of Cell Science, vol. 113, no. 12, pp. 2129–2138, 2000.
- X. Y. Wang, Y. Yin, H. Yuan, T. Sakamaki, H. Okano, and R. I. Glazer, “Musashi1 modulates mammary progenitor cell expansion through proliferin-mediated activation of the Wnt and Notch pathways,” Molecular and Cellular Biology, vol. 28, no. 11, pp. 3589–3599, 2008.
- F. Varnat, B. B. Ten Heggeler, P. Grisel et al., “PPAR/ regulates paneth cell differentiation via controlling the hedgehog signaling pathway,” Gastroenterology, vol. 131, no. 2, pp. 538–553, 2006.
- Y. Li, B. Welm, K. Podsypanina et al., “Evidence that transgenes encoding components of the Wnt signaling pathway preferentially induce mammary cancers from progenitor cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 26, pp. 15853–15858, 2003.
Copyright © 2008 Robert I. Glazer et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.