Peroxisome proliferator-activated receptor gamma and BRCA1

in Endocrine-Related Cancer
Correspondence should be addressed to P A Furth: paf3@georgetown.edu

Peroxisome proliferator-activated receptor gamma agonists have been proposed as breast cancer preventives. Individuals who carry a mutated copy of BRCA1, DNA repair-associated gene, are at increased risk for development of breast cancer. Published data in the field suggest there could be interactions between peroxisome proliferator-activated receptor gamma and BRCA1 that could influence the activity of peroxisome proliferator-activated receptor gamma agonists for prevention. This review explores these possible interactions between peroxisome proliferator-activated receptor gamma, peroxisome proliferator-activated receptor gamma agonists and BRCA1 and discusses feasible experimental directions to provide more definitive information on the potential connections.

Abstract

Peroxisome proliferator-activated receptor gamma agonists have been proposed as breast cancer preventives. Individuals who carry a mutated copy of BRCA1, DNA repair-associated gene, are at increased risk for development of breast cancer. Published data in the field suggest there could be interactions between peroxisome proliferator-activated receptor gamma and BRCA1 that could influence the activity of peroxisome proliferator-activated receptor gamma agonists for prevention. This review explores these possible interactions between peroxisome proliferator-activated receptor gamma, peroxisome proliferator-activated receptor gamma agonists and BRCA1 and discusses feasible experimental directions to provide more definitive information on the potential connections.

Interactions between PPARG and BRCA1

BRCA1, DNA repair-associated gene (BRCA1), is one of the most highly associated cancer susceptibility genes, principally with breast and ovarian cancer (Turnbull et al. 2018). Currently recommended preventive strategies are primarily surgical (Ludwig et al. 2016, Andrews & Mutch 2017) with evaluation of the relative effectiveness of the lifestyle-driven (Lammert et al. 2018) and hormonal approaches used, more generally, for reduction of breast cancer risk (Pujol et al. 2012, Phillips et al. 2013, Dabydeen et al. 2015, Alothman et al. 2017) considered more investigational.

Molecular studies have identified dysregulation of TNF receptor superfamily member 11a (RANK)/TNF superfamily member 11 (RANKL) and nuclear factor NF-kappa-B p105 subunit (NFKB1) as possible intersecting pathways with BRCA1 mutation-related breast cancer pathophysiology that may be approachable with pharmacologic chemoprevention (Sigl et al. 2016, Kotsopoulos et al. 2017, Nolan et al. 2017).

Questions arise as to other possible interacting signaling pathways in cancer prevention. Peroxisome proliferator-activated receptor gamma (PPARG), a member of the PPAR family of nuclear hormone transactivators, functions as a heterodimer with retinoid X receptor in normal physiology and development (Derosa et al. 2018). It has been characterized as a potential therapeutic target for cancer therapy and prevention (Yun et al. 2018).

PPARG ligands have been variously considered as potential chemopreventives as well as cancer therapeutics (Peters et al. 2012). This class of drugs is also considered for treatment of diabetes and cardiovascular disease. Considerations of relative efficacy vs potential side- and off-target effects have not only tempered enthusiasm for the drug class but also stimulated the synthesis and investigation of new generation PPARG therapeutic ligands and inhibitors (Ahmed et al. 2007, Rubenstrunk et al. 2007, Youssef & Badr 2013, Chandra et al. 2017). Phase 1 studies of efatutazone, a more recently developed and highly selective peroxisome proliferator-activated receptor gamma (PPARγ) agonist that can be delivered orally, demonstrated an acceptable safety profile for cancer therapy, alone and in combination with other drugs (Pishvaian et al. 2012, Esteva et al. 2013, Smallridge et al. 2013, Komatsu et al. 2014, Murakami et al. 2014). Rosiglitazone was investigated in a pilot study in breast cancer where safety and systemic biological activity were documented, but there was no significant evidence of efficacy (Yee et al. 2007).

Experimental animal in vivo studies have yielded mixed results on efficacy for cancer chemoprevention with a PPARG agonist. It is challenging to derive a clear answer from these investigations as studies have been performed in a diverse range of rodent cancer models, employed different PPARG agonists, utilized a variety of dosing schedules and were not always investigated as single agents. In addition, pharmacological intervention is initiated at different time points relative to cancer initiation and study durations are mixed. Positive impacts provide support for the principle of PPARG agonist chemoprevention (Kocdor et al. 2009, Li & Brown 2009, McCormick et al. 2015, Ory et al. 2018) but when significant effects are limited to hyperplasia and/or preneoplasia, alterations in cancer histology and/or mean tumor volume, there is less enthusiasm (Borbath et al. 2007, Wu et al. 2008, Skelhorne-Gross et al. 2012, Nakles et al. 2013, Bojková et al. 2016, Alothman et al. 2018). Occasional published studies report no effect at all (Yee et al. 2005).

In breast cancer prevention research one of the most highly targeted groups for development of new therapeutic approaches is women carrying a BRCA1 mutation. In vitro and in vivo molecular and genetic research provide potential intersecting points for BRCA1 and PPARG pathways, raising the possibility that BRCA1 status could influence response to therapy. Some (Pignatelli et al. 2003, Subbaramaiah et al. 2012, Apostoli et al. 2015), but not all (Rogue et al. 2010), published data indicates that BRCA1 expression can be increased by PPARG agonist therapy. Loss of PPARG in mammary adipocytes is reported to reduce Brca1 expression (Skelhorne-Gross et al. 2012). It has been suggested that PPARG agonists could reduce mammary cancer development through inhibition of aromatase expression that would be, at least in part, mediated through PPARG agonist driven Brca1 upregulation (Margalit et al. 2012).

From the other side, PPARG expression is reported upregulated specifically in BRCA1 mutant breast cancers (Heublein et al. 2017). When qualitatively assessed by immunohistochemistry at the protein level, PPARgamma remains detectable at the protein level in normal-appearing mammary epithelial cells with Brca1 exon 11 deletion in combination with Trp53 germ-line haploinsufficiency, with a relative increase and more uniform expression in adenocarcinomas (Nakles et al. 2013). One Phase 1 study showed that higher levels of PPARG correlate with an enhanced therapeutic response to the PPARG agonist efatutazone (Pishvaian et al. 2012) although this observation was not replicated in a second study (Komatsu et al. 2014). Interestingly, at the RNA level, loss of full-length Brca1 exon 11 in non-cancer cells is correlated with significantly decreased Pparg expression in cardiac muscle and whole mammary gland (Singh et al. 2013, Dabydeen et al. 2015).

Conclusions

In summary, it is not yet clear whether or not interactions between PPARG and BRCA1 modify the impact of a PPARgamma agonist used as a breast cancer chemopreventive. The PPARg agonist efatutazone is effective in significantly reducing mammary hyperplasia in mice with targeted deletion of Brca1 exon 11 in mammary epithelial cells, but there is no profound effect on invasive cancer incidence (Nakles et al. 2013, Alothman et al. 2018). However, preservation of one intact Brca1 allele is sufficient to significantly improve the preventive response. More uniformly positive effects from PPARG agonist exposure are reported in in vivo models of mammary cancer with two intact Brca1 genes (Kocdor et al. 2009, Ory et al. 2018). This could be an indication that initial levels of endogenous BRCA1 impact therapeutic response; however, this question still needs to be directly and specifically investigated in order to make a definitive statement (Fig. 1A). For example, therapeutic preventive response could be evaluated in a series of mouse models that develop mammary preneoplasia and cancer in the presence of two intact Brca1 genes as well as with one and two Brca1 alleles, perhaps in both the presence and absence of p53 heterozygosity, to evaluate the impact of specific genetic gain/loss determinants on response to efatutazone. Mammary-targeted Esr1 and CYP19A1 overexpression models are possible human pathophysiologically paralleled experimental directions to build Brca1 deletion models on to explore this question (Jones et al. 2008, Alamri et al. 2016). Polyoma middle T (PyMT), Wnt, HER2/Neu and simian virus 40 T antigen (TAg) overexpression models are opportunities to pursue studies of metastatic disease and interactions with other cancer-linked signaling pathways (Tilli et al. 2003, Fantozzi & Christofori 2006). The same ductal carcinoma in situ human xenograft model used to demonstrate efatutazone efficacy (Ory et al. 2018) could be re-tested with cells engineered to interrupt Brca1 expression or introduce specific clinically relevant mutations.

Figure 1

Download Figure

Figure 1

Questions to address for a more comprehensive understanding of peroxisome proliferator-activated receptor gamma and BRCA1 interactions. (A) Schematic illustrating the possibility that reduced levels of BRCA1 indicated by the vertical gradient of white to blue might influence the response to a PPARG agonist as indicated by the corresponding vertical gradient of white to orange labeled. (B) Schematic illustrating how the impact of a possible increase in BRCA1 expression levels indicated by the horizontal white to blue gradient mediated by exposure to a PPARG agonist could be determined to be related or unrelated to downstream PPARG agonist activity by experimentally blocking the BRCA1 increase. (C) Schematic illustrating the possibility that reduced BRCA1 levels indicated by the horizontal blue to white gradient could correspond to reduced PPARG levels indicated by the horizontal green to white gradient resulted in a reduced response to a PPARG agonist indicated by the horizontal orange to white gradient.

Citation: Endocrine-Related Cancer 26, 2; 10.1530/ERC-18-0449

A second question is whether or not upregulation of normal full-length BRCA1 expression levels contribute to PPARG agonist efficacy (Fig. 1B). Before this question can be clearly answered, researchers, however, need to establish whether or not BRCA1 expression is, in fact, uniformly and reproducibly upregulated by PPARG agonists. A related issue is whether or not levels of normal BRCA1 expression are sufficiently upregulated when a second allele contains a BRCA1 mutation, as occurs in the clinical setting. At present BRCA1 expression levels have not been uniformly reported in published studies of PPARG agonist therapy; however, it is possible that potential publication bias against negative or less marked results could have influenced reporting (Diaz-Cruz et al. 2006, Mlinarić et al. 2017). Disparate results that may have been found could be due to differences between the pharmacology of specific PPARG agonists, dose and schedule, timing of measurement and even acquired differences between cell lines or incorrect cell line identification as authentication of cell lines has only more recently been recognized as an important component of experimental design (Almeida et al. 2016). Even after recognizing all these challenges, from an experimental point of view, it is still feasible to design a mechanistic experiment using a panel of relevant normal, premalignant and malignant mammary human epithelial cell lines and primary cells to compare reproducibility of BRCA1 upregulation in different experimental reagents, establish if there are dose–response relationships, and evaluate both short- and longer-term exposures. Once optimal clinically relevant conditions are established, one could then test if blocking BRCA1 upregulation would modify impact of PPARG agonist therapy. In cell lines and primary material theoretically this could be accomplished with either genetic deletion of BRCA1 or siRNA or related approaches with read-out of PPARG agonist activity centering on downstream genes and signaling pathways as well as cellular morphology and behavior.

A third question is whether or not loss of normal BRCA1 function and/or expression impact PPARG expression levels (Fig. 1C). Published data are insufficient to answer this question as seemingly conflicting initial studies reporting reduced expression in cardiomyocytes and mammary tissue (Singh et al. 2013, Dabydeen et al. 2015) with loss of full-length Brca1 and increased levels in human breast cancers carrying a BRCA1 mutation (Heublein et al. 2017) have not yet been rigorously reproduced. Theoretically both observations could be true as loss of full-length Brca1 is not the same as BRCA1 mutation, the former studies are in mouse tissues and the later in human tissue, and RNA was examined in the mice and protein in the humans but additional work examining both RNA and protein are needed to clarify the issues. BRCA1 can play a role in transcriptional regulation (Mullan et al. 2006). Understanding the biology could be significant as there have been some suggestions that higher levels of PPARG expression could serve as a biomarker predictive of a positive response to a PPARG agonist (Pishvaian et al. 2012). An interesting speculation is whether or not a PPARG-mediated increase in BRCA1 expression levels could secondarily be associated with increased PPARG expression levels that would then contribute to an enhanced response to a PPARG agonist. The impact of BRCA1 deletion on PPARG mRNA and protein expression could be approached utilizing a panel of mammary epithelial cell lines and primary cells representing human normal, premalignant and malignant cells to assess both if PPARG expression levels are altered by loss of mutation of BRCA1, and if this occurs reproducibly across different cell lines and stages of cancer development.

Appropriate experimentation in human tissues and in vitro and in vivo model systems is merited when the promise of current therapeutic PPARG agonists is sufficiently convincing (Ferrari et al. 2016, Wang et al. 2016, Vella et al. 2017). The impact of specific BRCA1 variants on PPARG expression levels, signaling and downstream gene regulatory networks could be assessed with specific mutation and variant targeting (Findlay et al. 2018). Experiments focusing on the impact of functional BRCA1 haploinsufficiency in the presence of different mutations could be performed (Sedic & Kuperwasser 2016). Biological effects of known PPARG functions related to cell growth and differentiation could be stringently examined in the presence and absence of BRCA1. Measurements of downstream gene regulatory networks that follow PPARG activation could be evaluated and compared to determine if there were significant differences correlated with Brca1 gene dosage in murine cancer prevention models (Savic et al. 2016, Alothman et al. 2017, 2018).

There are additional questions that could also be approached. For example, the majority of published data to date has focused on RNA expression differences but newly designed studies could examine whether or not PPARG agonists reproducibly increase BRCA1 protein expression, follow-up with assessment of the biological and/or pathogenic significance and explore protein-based and metabolic interactions. Studies in which BRCA1 expression levels are deliberately varied should be correlated with assessment of PPARG levels and intentional manipulation of PPARG levels performed to assess how combinations of changes in expression of BRCA1 and PPARG impact response to specific PPARG agonists. Dose–response experiments might elucidate whether or not response to a PPARG agonist is a threshold event at the cellular level, occurring at the same magnitude once that expression threshold has been reached, even with low versus high PPARG levels, or differentially regulated at different PPARG expression levels. Finally, targeted mechanistically based molecular studies examining PPARG agonists might also reveal possible opportunities for rational combination therapy for breast cancer prevention (Johnson & Brown 2010).

Declaration of interest

The author declares that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.

Funding

This work was supported by National Institutes of Health, National Cancer Institute RO1 CA112176 (P A F) and 5P30CA051008.

References

  • AhmedWZiouzenkovaOBrownJDevchandPFrancisSKadakiaMKandaTOrasanuGSharlachMZandbergenF 2007 PPARs and their metabolic modulation: new mechanisms for transcriptional regulation? Journal of Internal Medicine 262 184198. (https://doi.org/10.1111/j.1365-2796.2007.01825.x)

  • AlamriAMGroeneveldSWangWZhongXKallakuryBHennighausenLFurthPA 2016 Primary cancer cell culture: mammary-optimized vs conditional reprogramming. Endocrine-Related Cancer 23 535554. (https://doi.org/10.1530/ERC-16-0071)

  • AlmeidaJLColeKDPlantAL 2016 Standards for cell line authentication and beyond. PLOS Biology 14 e1002476. (https://doi.org/10.1371/journal.pbio.1002476)

  • AlothmanSJWangWGoerlitzDSIslamMZhongXKishoreAAzharRIKallakuryBVFurthPA 2017 Responsiveness of Brca1 and Trp53 deficiency-induced mammary preneoplasia to selective estrogen modulators versus an aromatase inhibitor in Mus musculus. Cancer Prevention Research 10 244254. (https://doi.org/10.1158/1940-6207.CAPR-16-0268)

  • AlothmanSJWangWChaoSKallakuryBVDiaz-CruzESFurthPA 2018 Differential efatutazone’s impact on mammary neoplasia dependent upon Brca1 dose. Endocrine-Related Cancer 25 L53L57. (https://doi.org/10.1530/ERC-18-0299)

  • AndrewsLMutchDG 2017 Hereditary Ovarian Cancer and Risk Reduction. Best Practice and Research Clinical Obstetrics and Gynaecology 41 3148. (https://doi.org/10.1016/j.bpobgyn.2016.10.017)

  • ApostoliAJRocheJMSchneiderMMSenGuptaSKDiLenaMARubinoREPetersonNTNicolCJB 2015 Opposing roles for mammary epithelial-specific PPARγ signaling and activation during breast tumour progression. Molecular Cancer 14 85. (https://doi.org/10.1186/s12943-015-0347-8)

  • BojkováBOrendášPKajoKKubatkaPVýbohováDBálentováSKružliakPZulliADemečkováVPéčM 2016 Role of high-fat diet on the effect of pioglitazone and melatonin in a rat model of breast cancer. European Journal of Cancer Prevention 25 395403. (https://doi.org/10.1097/CEJ.0000000000000195)

  • BorbathILeclercqIMoulinPSempouxCHorsmansY 2007 The PPARgamma agonist pioglitazone inhibits early neoplastic occurrence in the rat liver. European Journal of Cancer 43 17551763. (https://doi.org/10.1016/j.ejca.2007.05.005)

  • ChandraMMiriyalaSPanchatcharamM 2017 PPARγ and its role in cardiovascular diseases. PPAR Research 2017 6404638. (https://doi.org/10.1155/2017/6404638)

  • DabydeenSAKangKDíaz-CruzESAlamriAAxelrodMLBoukerKBAl-KharbooshRClarkeRHennighausenLFurthPA 2015 Comparison of tamoxifen and letrozole response in mammary preneoplasia of ER and aromatase overexpressing mice defines an immune-associated gene signature linked to tamoxifen resistance. Carcinogenesis 36 122132. (https://doi.org/10.1093/carcin/bgu237)

  • DerosaGSahebkarAMaffioliP 2018 The role of various peroxisome proliferator-activated receptors and their ligands in clinical practice. Journal of Cellular Physiology 233 153161. (https://doi.org/10.1002/jcp.25804)

  • Diaz-CruzESRosenEMGrubbsCJFurthPA 2006 The effect of the PPARγ ligand rosiglitazone on BRCA1 gene expression in mice. Cancer Research 66 493493. (available at: http://cancerres.aacrjournals.org/content/66/8_Supplement/493.1)

  • EstevaFJMoulderSLGonzalez-AnguloAMEnsorJMurrayJLGreenMCKoenigKBLeeM-HHortobagyiGNYeungS-C 2013 Phase I trial of exemestane in combination with metformin and rosiglitazone in nondiabetic obese postmenopausal women with hormone receptor-positive metastatic breast cancer. Cancer Chemotherapy and Pharmacology 71 6372. (https://doi.org/10.1007/s00280-012-1977-9)

  • FantozziAChristoforiG 2006 Mouse models of breast cancer metastasis. Breast Cancer Research 8 212. (https://doi.org/10.1186/bcr1530)

  • FerrariSMMaterazziGBaldiniEUlisseSMiccoliPAntonelliAFallahiP 2016 Antineoplastic effects of PPARγ agonists, with a special focus on thyroid cancer. Current Medicinal Chemistry 23 636649. (https://doi.org/10.2174/0929867323666160203114607)

  • FindlayGMDazaRMMartinBZhangMDLeithAPGasperiniMJanizekJDHuangXStaritaLMShendureJ 2018 Accurate classification of BRCA1 variants with saturation genome editing. Nature 562 217222. (https://doi.org/10.1038/s41586-018-0461-z)

  • HeubleinSMayrDMeindlAKircherAJeschkeUDitschN 2017 Vitamin D receptor, Retinoid X receptor and peroxisome proliferator-activated receptor γ are overexpressed in BRCA1 mutated breast cancer and predict prognosis. Journal of Experimental and Clinical Cancer Research 36 57. (https://doi.org/10.1186/s13046-017-0517-1)

  • JohnsonKABrownPH 2010 Drug development for cancer chemoprevention: focus on molecular targets. Seminars in Oncology 37 345358. (https://doi.org/10.1053/j.seminoncol.2010.05.012)

  • JonesLPTilliMTAssefniaSTorreKHalamaEDParrishARosenEMFurthPA 2008 Activation of estrogen signaling pathways collaborates with loss of Brca1 to promote development of ERalpha-negative and ER-alpha-positive mammary preneoplasia and cancer. Oncogene 27 794802. (https://doi.org/10.1038/sj.onc.1210674

  • KocdorHKocdorMACandaTGurelDCehreliRYilmazOAlakavuklarMGunerG 2009 Chemopreventive efficacies of rosiglitazone, fenretinide and their combination against rat mammary carcinogenesis. Clinical and Translational Oncology 11 243249. (https://doi.org/10.1007/s12094-009-0347-5)

  • KomatsuYYoshinoTYamazakiKYukiSMachidaNSasakiTHyodoIYachiYOnumaHOhtsuA 2014 Phase 1 study of efatutazone, a novel oral peroxisome proliferator-activated receptor gamma agonist, in combination with FOLFIRI as second-line therapy in patients with metastatic colorectal cancer. Investigational New Drugs 32 473480. (https://doi.org/10.1007/s10637-013-0056-3)

  • KotsopoulosJSingerCNarodSA 2017 Can we prevent BRCA1-associated breast cancer by RANKL inhibition? Breast Cancer Research and Treatment 161 1116. (https://doi.org/10.1007/s10549-016-4029-z)

  • LammertJGrillSKiechleM 2018 Modifiable lifestyle factors: opportunities for (hereditary) breast cancer prevention - a narrative review. Breast Care 13 109114. (https://doi.org/10.1159/000488995)

  • LiYBrownPH 2009 Prevention of ER-negative breast cancer. Recent Results in Cancer Research 181 121134. (https://doi.org/10.1007/978-3-540-69297-3_13)

  • LudwigKKNeunerJButlerAGeurtsJLKongAL 2016 Risk reduction and survival benefit of prophylactic surgery in BRCA mutation carriers, a systematic review. American Journal of Surgery 212 660669. (https://doi.org/10.1016/j.amjsurg.2016.06.010)

  • MargalitOWangDDuboisRN 2012 PPARγ agonists target aromatase via both PGE2 and BRCA1. Cancer Prevention Research 5 11691172. (https://doi.org/10.1158/1940-6207.CAPR-12-0365)

  • McCormickDLHornTLJohnsonWDPengXLubetRASteeleVE 2015 Suppression of rat oral carcinogenesis by agonists of peroxisome proliferator activated receptor γ. PLoS ONE 10 e0141849. (https://doi.org/10.1371/journal.pone.0141849)

  • MlinarićAHorvatMŠupak SmolčićV 2017 Dealing with the positive publication bias: why you should really publish your negative results. Biochemia Medica 27. (https://doi.org/10.11613/BM.2017.030201)

  • MullanPBQuinnJEHarkinDP 2006 The role of BRCA1 in transcriptional regulation and cell cycle control. Oncogene 25 58545863. (https://doi.org/10.1038/sj.onc.1209872)

  • MurakamiHOnoATakahashiTOnozawaYTsushimaTYamazakiKJikohTBokuNYamamotoN 2014 Phase I study of Efatutazone, an oral PPARγ agonist, in patients with metastatic solid tumors. Anticancer Research 34 51335141. (http://ar.iiarjournals.org/content/34/9/5133.full)

  • NaklesREKallakuryBVSFurthPA 2013 The PPARγ agonist efatutazone increases the spectrum of well-differentiated mammary cancer subtypes initiated by loss of full-length BRCA1 in association with TP53 haploinsufficiency. American Journal of Pathology 182 19761985. (https://doi.org/10.1016/j.ajpath.2013.02.006)

  • NolanELindemanGJVisvaderJE 2017 Out-RANKing BRCA1 in mutation carriers. Cancer Research 77 595600. (https://doi.org/10.1158/0008-5472.CAN-16-2025)

  • OryVKietzmanWBBoeckelmanJKallakuryBVWellsteinAFurthPARiegelAT 2018 The PPARγ agonist efatutazone delays invasive progression and induces differentiation of ductal carcinoma in situ. Breast Cancer Research and Treatment 169 4757. (https://doi.org/10.1007/s10549-017-4649-y)

  • PetersJMShahYMGonzalezFJ 2012 The role of peroxisome proliferator-activated receptors in carcinogenesis and chemoprevention. Nature Reviews. Cancer 12 181195. (https://doi.org/10.1038/nrc3214)

  • PhillipsK-AMilneRLRookusMADalyMBAntoniouACPeockSFrostDEastonDFEllisSFriedlanderML 2013 Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. Journal of Clinical Oncology 31 30913099. (https://doi.org/10.1200/JCO.2012.47.8313)

  • PignatelliMCoccaCSantosAPerez-CastilloA 2003 Enhancement of BRCA1 gene expression by the peroxisome proliferator-activated receptor gamma in the MCF-7 breast cancer cell line. Oncogene 22 54465450. (https://doi.org/10.1038/sj.onc.1206824)

  • PishvaianMJMarshallJLWagnerAJHwangJJMalikSCotarlaIDeekenJFHeARDanielHHalimA-B 2012 A phase 1 study of efatutazone, an oral peroxisome proliferator-activated receptor gamma agonist, administered to patients with advanced malignancies. Cancer 118 54035413. (https://doi.org/10.1002/cncr.27526)

  • PujolPLassetCBerthetPDugastCDelalogeSFrickerJ-PTennevetIChabbert-BuffetNThisPBaudryK 2012 Uptake of a randomized breast cancer prevention trial comparing letrozole to placebo in BRCA1/2 mutations carriers: the LIBER trial. Familial Cancer 11 7784. (https://doi.org/10.1007/s10689-011-9484-4)

  • RogueASpireCBrunMClaudeNGuillouzoA 2010 Gene expression changes induced by PPAR gamma agonists in animal and human liver. PPAR Research 2010 325183. (https://doi.org/10.1155/2010/325183)

  • RubenstrunkAHanfRHumDWFruchartJ-CStaelsB 2007 Safety issues and prospects for future generations of PPAR modulators. Biochimica et Biophysica Acta 1771 10651081. (https://doi.org/10.1016/j.bbalip.2007.02.003)

  • SavicDRamakerRCRobertsBSDeanECBurwellTCMeadowsSKCooperSJGarabedianMJGertzJMyersRM 2016 Distinct gene regulatory programs define the inhibitory effects of liver X receptors and PPARG on cancer cell proliferation. Genome Medicine 8 74. (https://doi.org/10.1186/s13073-016-0328-6)

  • SedicMKuperwasserC 2016 BRCA1-hapoinsufficiency: Unraveling the molecular and cellular basis for tissue-specific cancer. Cell Cycle 15 621627. (https://doi.org/10.1080/15384101.2016.1141841)

  • SiglVOwusu-BoaiteyKJoshiPAKavirayaniAWirnsbergerGNovatchkovaMKozieradzkiISchramekDEdokobiNHerslJ 2016 RANKL/RANK control Brca1 mutation-driven mammary tumors. Cell Research 26 761774. (https://doi.org/10.1038/cr.2016.69)

  • SinghKKShuklaPCYanagawaBQuanALovrenFPanYWaggCSTeohHLopaschukGDVermaS 2013 Regulating cardiac energy metabolism and bioenergetics by targeting the DNA damage repair protein BRCA1. Journal of Thoracic and Cardiovascular Surgery 146 702709. (https://doi.org/10.1016/j.jtcvs.2012.12.046)

  • Skelhorne-GrossGReidALApostoliAJDiLenaMARubinoREPetersonNTSchneiderMSenGuptaSKGonzalezFJNicolCJB 2012 Stromal adipocyte PPARγ protects against breast tumorigenesis. Carcinogenesis 33 14121420. (https://doi.org/10.1093/carcin/bgs173)

  • SmallridgeRCCoplandJABroseMSWadsworthJTHouvrasYMenefeeMEBibleKCShahMHGramzaAWKlopperJP 2013 Efatutazone, an oral PPAR-γ agonist, in combination with paclitaxel in anaplastic thyroid cancer: results of a multicenter phase 1 trial. Journal of Clinical Endocrinology and Metabolism 98 23922400. (https://doi.org/10.1210/jc.2013-1106)

  • SubbaramaiahKHoweLRZhouXKYangPHudisCAKopelovichLDannenbergAJ 2012 Pioglitazone, a PPARγ agonist, suppresses CYP19 transcription: evidence for involvement of 15-hydroxyprostaglandin dehydrogenase and BRCA1. Cancer Prevention Research 5 11831194. (https://doi.org/10.1158/1940-6207.CAPR-12-0201)

  • TilliMTFrechMSSteedMEHruskaKSJohnsonMDFlawsJAFurthPA 2003 Introduction of estrogen receptor-α into the tTA/TAg conditional mouse model precipitates the development of estrogen-responsive mammary adenocarcinoma. American Journal of Pathology 163 17131719. (https://doi.org/10.1016/S0002-9440(10)63529-8)

  • TurnbullCSudAHoulstonRS 2018 Cancer genetics, precision prevention and a call to action. Nature Genetics 50 12121218. (https://doi.org/10.1038/s41588-018-0202-0)

  • VellaVNicolosiMLGiulianoSBellomoMBelfioreAMalaguarneraR 2017 PPAR-γ agonists as antineoplastic agents in cancers with dysregulated IGF axis. Frontiers in Endocrinology 8 31. (https://doi.org/10.3389/fendo.2017.00031)

  • WangSDoughertyEJDannerRL 2016 PPARγ signaling and emerging opportunities for improved therapeutics. Pharmacological Research 111 7685. (https://doi.org/10.1016/j.phrs.2016.02.028)

  • WuWCelestinoJMilamMRSchmelerKMBroaddusRREllensonLHLuKH 2008 Primary chemoprevention of endometrial hyperplasia with the peroxisome proliferator-activated receptor gamma agonist rosiglitazone in the PTEN heterozygote murine model. International Journal of Gynecological Cancer 18 329338. (https://doi.org/10.1111/j.1525-1438.2007.01002.x)

  • YeeLDYoungDCRosolTJVanbuskirkAMClintonSK 2005 Dietary (n-3) polyunsaturated fatty acids inhibit HER-2/neu-induced breast cancer in mice independently of the PPARgamma ligand rosiglitazone. Journal of Nutrition 135 983988. (https://doi.org/10.1093/jn/135.5.983)

  • YeeLDWilliamsNWenPYoungDCLesterJJohnsonMVFarrarWBWalkerMJPovoskiSPSusterS 2007 Pilot study of rosiglitazone therapy in women with breast cancer: effects of short-term therapy on tumor tissue and serum markers. Clinical Cancer Research 13 246252. (https://doi.org/10.1158/1078-0432.CCR-06-1947)

  • YoussefJBadrMZ 2013 PPARs: history and advances. Methods in Molecular Biology 952 16. (https://doi.org/10.1007/978-1-62703-155-4_1)

  • YunS-HHanS-HParkJ-I 2018 Peroxisome proliferator-activated receptor γ and PGC-1α in cancer: dual actions as tumor promoter and suppressor. PPAR Research. 2018 6727421. (https://doi.org/10.1155/2018/6727421)

If the inline PDF is not rendering correctly, you can download the PDF file here.

 

An official journal of

Society for Endocrinology

Article Information

Metrics

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 232 232 157
PDF Downloads 19 19 14

Altmetrics

Related Articles

Figures

  • View in gallery

    Questions to address for a more comprehensive understanding of peroxisome proliferator-activated receptor gamma and BRCA1 interactions. (A) Schematic illustrating the possibility that reduced levels of BRCA1 indicated by the vertical gradient of white to blue might influence the response to a PPARG agonist as indicated by the corresponding vertical gradient of white to orange labeled. (B) Schematic illustrating how the impact of a possible increase in BRCA1 expression levels indicated by the horizontal white to blue gradient mediated by exposure to a PPARG agonist could be determined to be related or unrelated to downstream PPARG agonist activity by experimentally blocking the BRCA1 increase. (C) Schematic illustrating the possibility that reduced BRCA1 levels indicated by the horizontal blue to white gradient could correspond to reduced PPARG levels indicated by the horizontal green to white gradient resulted in a reduced response to a PPARG agonist indicated by the horizontal orange to white gradient.

References

AhmedWZiouzenkovaOBrownJDevchandPFrancisSKadakiaMKandaTOrasanuGSharlachMZandbergenF 2007 PPARs and their metabolic modulation: new mechanisms for transcriptional regulation? Journal of Internal Medicine 262 184198. (https://doi.org/10.1111/j.1365-2796.2007.01825.x)

AlamriAMGroeneveldSWangWZhongXKallakuryBHennighausenLFurthPA 2016 Primary cancer cell culture: mammary-optimized vs conditional reprogramming. Endocrine-Related Cancer 23 535554. (https://doi.org/10.1530/ERC-16-0071)

AlmeidaJLColeKDPlantAL 2016 Standards for cell line authentication and beyond. PLOS Biology 14 e1002476. (https://doi.org/10.1371/journal.pbio.1002476)

AlothmanSJWangWGoerlitzDSIslamMZhongXKishoreAAzharRIKallakuryBVFurthPA 2017 Responsiveness of Brca1 and Trp53 deficiency-induced mammary preneoplasia to selective estrogen modulators versus an aromatase inhibitor in Mus musculus. Cancer Prevention Research 10 244254. (https://doi.org/10.1158/1940-6207.CAPR-16-0268)

AlothmanSJWangWChaoSKallakuryBVDiaz-CruzESFurthPA 2018 Differential efatutazone’s impact on mammary neoplasia dependent upon Brca1 dose. Endocrine-Related Cancer 25 L53L57. (https://doi.org/10.1530/ERC-18-0299)

AndrewsLMutchDG 2017 Hereditary Ovarian Cancer and Risk Reduction. Best Practice and Research Clinical Obstetrics and Gynaecology 41 3148. (https://doi.org/10.1016/j.bpobgyn.2016.10.017)

ApostoliAJRocheJMSchneiderMMSenGuptaSKDiLenaMARubinoREPetersonNTNicolCJB 2015 Opposing roles for mammary epithelial-specific PPARγ signaling and activation during breast tumour progression. Molecular Cancer 14 85. (https://doi.org/10.1186/s12943-015-0347-8)

BojkováBOrendášPKajoKKubatkaPVýbohováDBálentováSKružliakPZulliADemečkováVPéčM 2016 Role of high-fat diet on the effect of pioglitazone and melatonin in a rat model of breast cancer. European Journal of Cancer Prevention 25 395403. (https://doi.org/10.1097/CEJ.0000000000000195)

BorbathILeclercqIMoulinPSempouxCHorsmansY 2007 The PPARgamma agonist pioglitazone inhibits early neoplastic occurrence in the rat liver. European Journal of Cancer 43 17551763. (https://doi.org/10.1016/j.ejca.2007.05.005)

ChandraMMiriyalaSPanchatcharamM 2017 PPARγ and its role in cardiovascular diseases. PPAR Research 2017 6404638. (https://doi.org/10.1155/2017/6404638)

DabydeenSAKangKDíaz-CruzESAlamriAAxelrodMLBoukerKBAl-KharbooshRClarkeRHennighausenLFurthPA 2015 Comparison of tamoxifen and letrozole response in mammary preneoplasia of ER and aromatase overexpressing mice defines an immune-associated gene signature linked to tamoxifen resistance. Carcinogenesis 36 122132. (https://doi.org/10.1093/carcin/bgu237)

DerosaGSahebkarAMaffioliP 2018 The role of various peroxisome proliferator-activated receptors and their ligands in clinical practice. Journal of Cellular Physiology 233 153161. (https://doi.org/10.1002/jcp.25804)

Diaz-CruzESRosenEMGrubbsCJFurthPA 2006 The effect of the PPARγ ligand rosiglitazone on BRCA1 gene expression in mice. Cancer Research 66 493493. (available at: http://cancerres.aacrjournals.org/content/66/8_Supplement/493.1)

EstevaFJMoulderSLGonzalez-AnguloAMEnsorJMurrayJLGreenMCKoenigKBLeeM-HHortobagyiGNYeungS-C 2013 Phase I trial of exemestane in combination with metformin and rosiglitazone in nondiabetic obese postmenopausal women with hormone receptor-positive metastatic breast cancer. Cancer Chemotherapy and Pharmacology 71 6372. (https://doi.org/10.1007/s00280-012-1977-9)

FantozziAChristoforiG 2006 Mouse models of breast cancer metastasis. Breast Cancer Research 8 212. (https://doi.org/10.1186/bcr1530)

FerrariSMMaterazziGBaldiniEUlisseSMiccoliPAntonelliAFallahiP 2016 Antineoplastic effects of PPARγ agonists, with a special focus on thyroid cancer. Current Medicinal Chemistry 23 636649. (https://doi.org/10.2174/0929867323666160203114607)

FindlayGMDazaRMMartinBZhangMDLeithAPGasperiniMJanizekJDHuangXStaritaLMShendureJ 2018 Accurate classification of BRCA1 variants with saturation genome editing. Nature 562 217222. (https://doi.org/10.1038/s41586-018-0461-z)

HeubleinSMayrDMeindlAKircherAJeschkeUDitschN 2017 Vitamin D receptor, Retinoid X receptor and peroxisome proliferator-activated receptor γ are overexpressed in BRCA1 mutated breast cancer and predict prognosis. Journal of Experimental and Clinical Cancer Research 36 57. (https://doi.org/10.1186/s13046-017-0517-1)

JohnsonKABrownPH 2010 Drug development for cancer chemoprevention: focus on molecular targets. Seminars in Oncology 37 345358. (https://doi.org/10.1053/j.seminoncol.2010.05.012)

JonesLPTilliMTAssefniaSTorreKHalamaEDParrishARosenEMFurthPA 2008 Activation of estrogen signaling pathways collaborates with loss of Brca1 to promote development of ERalpha-negative and ER-alpha-positive mammary preneoplasia and cancer. Oncogene 27 794802. (https://doi.org/10.1038/sj.onc.1210674

KocdorHKocdorMACandaTGurelDCehreliRYilmazOAlakavuklarMGunerG 2009 Chemopreventive efficacies of rosiglitazone, fenretinide and their combination against rat mammary carcinogenesis. Clinical and Translational Oncology 11 243249. (https://doi.org/10.1007/s12094-009-0347-5)

KomatsuYYoshinoTYamazakiKYukiSMachidaNSasakiTHyodoIYachiYOnumaHOhtsuA 2014 Phase 1 study of efatutazone, a novel oral peroxisome proliferator-activated receptor gamma agonist, in combination with FOLFIRI as second-line therapy in patients with metastatic colorectal cancer. Investigational New Drugs 32 473480. (https://doi.org/10.1007/s10637-013-0056-3)

KotsopoulosJSingerCNarodSA 2017 Can we prevent BRCA1-associated breast cancer by RANKL inhibition? Breast Cancer Research and Treatment 161 1116. (https://doi.org/10.1007/s10549-016-4029-z)

LammertJGrillSKiechleM 2018 Modifiable lifestyle factors: opportunities for (hereditary) breast cancer prevention - a narrative review. Breast Care 13 109114. (https://doi.org/10.1159/000488995)

LiYBrownPH 2009 Prevention of ER-negative breast cancer. Recent Results in Cancer Research 181 121134. (https://doi.org/10.1007/978-3-540-69297-3_13)

LudwigKKNeunerJButlerAGeurtsJLKongAL 2016 Risk reduction and survival benefit of prophylactic surgery in BRCA mutation carriers, a systematic review. American Journal of Surgery 212 660669. (https://doi.org/10.1016/j.amjsurg.2016.06.010)

MargalitOWangDDuboisRN 2012 PPARγ agonists target aromatase via both PGE2 and BRCA1. Cancer Prevention Research 5 11691172. (https://doi.org/10.1158/1940-6207.CAPR-12-0365)

McCormickDLHornTLJohnsonWDPengXLubetRASteeleVE 2015 Suppression of rat oral carcinogenesis by agonists of peroxisome proliferator activated receptor γ. PLoS ONE 10 e0141849. (https://doi.org/10.1371/journal.pone.0141849)

MlinarićAHorvatMŠupak SmolčićV 2017 Dealing with the positive publication bias: why you should really publish your negative results. Biochemia Medica 27. (https://doi.org/10.11613/BM.2017.030201)

MullanPBQuinnJEHarkinDP 2006 The role of BRCA1 in transcriptional regulation and cell cycle control. Oncogene 25 58545863. (https://doi.org/10.1038/sj.onc.1209872)

MurakamiHOnoATakahashiTOnozawaYTsushimaTYamazakiKJikohTBokuNYamamotoN 2014 Phase I study of Efatutazone, an oral PPARγ agonist, in patients with metastatic solid tumors. Anticancer Research 34 51335141. (http://ar.iiarjournals.org/content/34/9/5133.full)

NaklesREKallakuryBVSFurthPA 2013 The PPARγ agonist efatutazone increases the spectrum of well-differentiated mammary cancer subtypes initiated by loss of full-length BRCA1 in association with TP53 haploinsufficiency. American Journal of Pathology 182 19761985. (https://doi.org/10.1016/j.ajpath.2013.02.006)

NolanELindemanGJVisvaderJE 2017 Out-RANKing BRCA1 in mutation carriers. Cancer Research 77 595600. (https://doi.org/10.1158/0008-5472.CAN-16-2025)

OryVKietzmanWBBoeckelmanJKallakuryBVWellsteinAFurthPARiegelAT 2018 The PPARγ agonist efatutazone delays invasive progression and induces differentiation of ductal carcinoma in situ. Breast Cancer Research and Treatment 169 4757. (https://doi.org/10.1007/s10549-017-4649-y)

PetersJMShahYMGonzalezFJ 2012 The role of peroxisome proliferator-activated receptors in carcinogenesis and chemoprevention. Nature Reviews. Cancer 12 181195. (https://doi.org/10.1038/nrc3214)

PhillipsK-AMilneRLRookusMADalyMBAntoniouACPeockSFrostDEastonDFEllisSFriedlanderML 2013 Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. Journal of Clinical Oncology 31 30913099. (https://doi.org/10.1200/JCO.2012.47.8313)

PignatelliMCoccaCSantosAPerez-CastilloA 2003 Enhancement of BRCA1 gene expression by the peroxisome proliferator-activated receptor gamma in the MCF-7 breast cancer cell line. Oncogene 22 54465450. (https://doi.org/10.1038/sj.onc.1206824)

PishvaianMJMarshallJLWagnerAJHwangJJMalikSCotarlaIDeekenJFHeARDanielHHalimA-B 2012 A phase 1 study of efatutazone, an oral peroxisome proliferator-activated receptor gamma agonist, administered to patients with advanced malignancies. Cancer 118 54035413. (https://doi.org/10.1002/cncr.27526)

PujolPLassetCBerthetPDugastCDelalogeSFrickerJ-PTennevetIChabbert-BuffetNThisPBaudryK 2012 Uptake of a randomized breast cancer prevention trial comparing letrozole to placebo in BRCA1/2 mutations carriers: the LIBER trial. Familial Cancer 11 7784. (https://doi.org/10.1007/s10689-011-9484-4)

RogueASpireCBrunMClaudeNGuillouzoA 2010 Gene expression changes induced by PPAR gamma agonists in animal and human liver. PPAR Research 2010 325183. (https://doi.org/10.1155/2010/325183)

RubenstrunkAHanfRHumDWFruchartJ-CStaelsB 2007 Safety issues and prospects for future generations of PPAR modulators. Biochimica et Biophysica Acta 1771 10651081. (https://doi.org/10.1016/j.bbalip.2007.02.003)

SavicDRamakerRCRobertsBSDeanECBurwellTCMeadowsSKCooperSJGarabedianMJGertzJMyersRM 2016 Distinct gene regulatory programs define the inhibitory effects of liver X receptors and PPARG on cancer cell proliferation. Genome Medicine 8 74. (https://doi.org/10.1186/s13073-016-0328-6)

SedicMKuperwasserC 2016 BRCA1-hapoinsufficiency: Unraveling the molecular and cellular basis for tissue-specific cancer. Cell Cycle 15 621627. (https://doi.org/10.1080/15384101.2016.1141841)

SiglVOwusu-BoaiteyKJoshiPAKavirayaniAWirnsbergerGNovatchkovaMKozieradzkiISchramekDEdokobiNHerslJ 2016 RANKL/RANK control Brca1 mutation-driven mammary tumors. Cell Research 26 761774. (https://doi.org/10.1038/cr.2016.69)

SinghKKShuklaPCYanagawaBQuanALovrenFPanYWaggCSTeohHLopaschukGDVermaS 2013 Regulating cardiac energy metabolism and bioenergetics by targeting the DNA damage repair protein BRCA1. Journal of Thoracic and Cardiovascular Surgery 146 702709. (https://doi.org/10.1016/j.jtcvs.2012.12.046)

Skelhorne-GrossGReidALApostoliAJDiLenaMARubinoREPetersonNTSchneiderMSenGuptaSKGonzalezFJNicolCJB 2012 Stromal adipocyte PPARγ protects against breast tumorigenesis. Carcinogenesis 33 14121420. (https://doi.org/10.1093/carcin/bgs173)

SmallridgeRCCoplandJABroseMSWadsworthJTHouvrasYMenefeeMEBibleKCShahMHGramzaAWKlopperJP 2013 Efatutazone, an oral PPAR-γ agonist, in combination with paclitaxel in anaplastic thyroid cancer: results of a multicenter phase 1 trial. Journal of Clinical Endocrinology and Metabolism 98 23922400. (https://doi.org/10.1210/jc.2013-1106)

SubbaramaiahKHoweLRZhouXKYangPHudisCAKopelovichLDannenbergAJ 2012 Pioglitazone, a PPARγ agonist, suppresses CYP19 transcription: evidence for involvement of 15-hydroxyprostaglandin dehydrogenase and BRCA1. Cancer Prevention Research 5 11831194. (https://doi.org/10.1158/1940-6207.CAPR-12-0201)

TilliMTFrechMSSteedMEHruskaKSJohnsonMDFlawsJAFurthPA 2003 Introduction of estrogen receptor-α into the tTA/TAg conditional mouse model precipitates the development of estrogen-responsive mammary adenocarcinoma. American Journal of Pathology 163 17131719. (https://doi.org/10.1016/S0002-9440(10)63529-8)

TurnbullCSudAHoulstonRS 2018 Cancer genetics, precision prevention and a call to action. Nature Genetics 50 12121218. (https://doi.org/10.1038/s41588-018-0202-0)

VellaVNicolosiMLGiulianoSBellomoMBelfioreAMalaguarneraR 2017 PPAR-γ agonists as antineoplastic agents in cancers with dysregulated IGF axis. Frontiers in Endocrinology 8 31. (https://doi.org/10.3389/fendo.2017.00031)

WangSDoughertyEJDannerRL 2016 PPARγ signaling and emerging opportunities for improved therapeutics. Pharmacological Research 111 7685. (https://doi.org/10.1016/j.phrs.2016.02.028)

WuWCelestinoJMilamMRSchmelerKMBroaddusRREllensonLHLuKH 2008 Primary chemoprevention of endometrial hyperplasia with the peroxisome proliferator-activated receptor gamma agonist rosiglitazone in the PTEN heterozygote murine model. International Journal of Gynecological Cancer 18 329338. (https://doi.org/10.1111/j.1525-1438.2007.01002.x)

YeeLDYoungDCRosolTJVanbuskirkAMClintonSK 2005 Dietary (n-3) polyunsaturated fatty acids inhibit HER-2/neu-induced breast cancer in mice independently of the PPARgamma ligand rosiglitazone. Journal of Nutrition 135 983988. (https://doi.org/10.1093/jn/135.5.983)

YeeLDWilliamsNWenPYoungDCLesterJJohnsonMVFarrarWBWalkerMJPovoskiSPSusterS 2007 Pilot study of rosiglitazone therapy in women with breast cancer: effects of short-term therapy on tumor tissue and serum markers. Clinical Cancer Research 13 246252. (https://doi.org/10.1158/1078-0432.CCR-06-1947)

YoussefJBadrMZ 2013 PPARs: history and advances. Methods in Molecular Biology 952 16. (https://doi.org/10.1007/978-1-62703-155-4_1)

YunS-HHanS-HParkJ-I 2018 Peroxisome proliferator-activated receptor γ and PGC-1α in cancer: dual actions as tumor promoter and suppressor. PPAR Research. 2018 6727421. (https://doi.org/10.1155/2018/6727421)

PubMed

Google Scholar