Anticancer Activities of PPARγ in Breast Cancer Are Context-Dependent
2013; Elsevier BV; Volume: 182; Issue: 6 Linguagem: Inglês
10.1016/j.ajpath.2013.03.005
ISSN1525-2191
Autores Tópico(s)Metabolism, Diabetes, and Cancer
ResumoIn this issue of The American Journal of Pathology, Nakles et al1Nakles R.E. Kallakury B.V.S. Furth P.A. Efatutazone, a PPARγ agonist, increases the spectrum of well-differentiated mammary cancer subtypes initiated by loss of full-length BRCA1 in association with p53 haploinsufficiency.Am J Pathol. 2013; 182: 1976-1985Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar used mouse mammary glands with null Brca1 and haplo-insufficient Trp53 as a tumor model to evaluate the effect of PPAR agonist efatutazone on mammary tumorigenesis. Mice were treated at age 4 months, so the findings could be more relevant to treatment rather than prevention. The authors found that, although efatutazone did not have a significant effect on the incidence of invasive tumors, it significantly reduced the incidence of non-invasive mammary tumor and promoted more differentiated histology in the tumors that formed. Efatutazone also reduced the prevalence of dense preneoplastic lesions including lobular growth and the number of hyperplastic alveolar nodules (HANs). Tumors from the efatutazone group had reduced expression of phosphor-AKT but not total AKT, and CDK6 was the only cell cycle regulator that was down-regulated. These findings not only provide insight but also help clarify several issues in an area that could lead to new therapy in the treatment of breast cancer. The peroxisome proliferator-activated receptor (PPAR) belongs to the nuclear receptor (NR) superfamily that includes estrogen receptors (ERs), retinoic acid receptors (RARs), retinoid X receptors (RXRs), and the vitamin D receptor (VDR). PPARγ is one of the PPARs that are expressed in different tissues. On the binding of its ligand, PPARγ heterodimerizes with RXR to form a complex that translocates into the nucleus, where the complex and its coactivators bind to gene promoters to regulate the transcription of PPARγ target genes. Known coactivators and corepressors of PPARγ include the histone acetyltransferase p300 (CBP), SRC-1, TEF2, Drip205 (Med220), and PGC-1. Binding of ligand to PPARγ usually leads to its dissociation from corepressors and association with coactivators.2Han S. Roman J. Peroxisome proliferator-activated receptor gamma: a novel target for cancer therapeutics?.Anticancer Drugs. 2007; 18: 237-244Crossref PubMed Scopus (108) Google Scholar PPARγ regulates different biological processes including adipocyte differentiation, glucose homeostasis, cell proliferation and differentiation, inflammation, apoptosis, angiogenesis, development, and carcinogenesis.3Lehrke M. Lazar M.A. The many faces of PPARgamma.Cell. 2005; 123: 993-999Abstract Full Text Full Text PDF PubMed Scopus (1156) Google Scholar, 4Sporn M.B. Suh N. Mangelsdorf D.J. Prospects for prevention and treatment of cancer with selective PPARgamma modulators (SPARMs).Trends Mol Med. 2001; 7: 395-400Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar The diverse functions of PPARγ are mediated by different group of genes that are known to regulate these processes, including those involved in cell cycle arrest, apoptosis, and DNA damage response.5Yu C. Markan K. Temple K.A. Deplewski D. Brady M.J. Cohen R.N. The nuclear receptor corepressors NCoR and SMRT decrease peroxisome proliferator-activated receptor gamma transcriptional activity and repress 3T3-L1 adipogenesis.J Biol Chem. 2005; 280: 13600-13605Crossref PubMed Scopus (175) Google Scholar, 6Van Laere S.J. Van den Eynden G.G. Van der Auwera I. Vandenberghe M. van Dam P. Van Marck E.A. van Golen K.L. Vermeulen P.B. Dirix L.Y. Identification of cell-of-origin breast tumor subtypes in inflammatory breast cancer by gene expression profiling.Breast Cancer Res Treat. 2006; 95: 243-255Crossref PubMed Scopus (100) Google Scholar After the widely used anti-diabetic thiazolidinedione (TZD) drugs were found to be ligands for PPARγ,7Lehmann J.M. Moore L.B. Smith-Oliver T.A. Wilkison W.O. Willson T.M. Kliewer S.A. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma).J Biol Chem. 1995; 270: 12953-12956Abstract Full Text Full Text PDF PubMed Scopus (3456) Google Scholar some natural ligands for PPARγ have been identified and used to elucidate the role of PPARγ in cellular functions both in vitro and in vivo.8Belvisi M.G. Hele D.J. Birrell M.A. Peroxisome proliferator-activated receptor gamma agonists as therapy for chronic airway inflammation.Eur J Pharmacol. 2006; 533: 101-109Crossref PubMed Scopus (121) Google Scholar Derivatives of TZD have also been developed with higher specificities and activities. The agonist used in this study, efatutazone (also called CS-7017 or RS5444), is a selective high-affinity TZD-class agonist of PPARγ. Efatutazone induces PPARγ-dependent transactivation but has no effect on the activation of either PPARα or PPARδ. In human tissues, the PPARG gene is expressed in normal cells and can undergo mutations in some cancers. For example, PPARG mutation has been detected in colon cancer and chromosomal translocation that produces an oncogenic fusion protein involving PPARγ; ie, PAX8–PPARγ, occurs in thyroid follicular carcinoma,9Lui W.O. Foukakis T. Liden J. Thoppe S.R. Dwight T. Hoog A. Zedenius J. Wallin G. Reimers M. Larsson C. Expression profiling reveals a distinct transcription signature in follicular thyroid carcinomas with a PAX8-PPAR(gamma) fusion oncogene.Oncogene. 2005; 24: 1467-1476Crossref PubMed Scopus (63) Google Scholar which suggests that PPARγ could be oncogenic. In breast cancer, however, the PPARG gene is not mutated. PPARγ is expressed in both normal and malignant mammary tissues and its expression level is often higher in cancer tissues.10Ditsch N. Vrekoussis T. Lenhard M. Ruhl I. Gallwas J. Weissenbacher T. Friese K. Mayr D. Makrigiannakis A. Jeschke U. Retinoid X receptor alpha (RXRalpha) and peroxisome proliferator-activated receptor gamma (PPARgamma) expression in breast cancer: an immunohistochemical study.In Vivo. 2012; 26: 87-92PubMed Google Scholar However, an increased expression in cancer cells does not necessarily mean an oncogenic role in tumor development. Therefore, there is no genetic evidence for either a tumor suppressor or an oncogenic function of PPARγ in breast cancer. The key finding of Nakles et al1Nakles R.E. Kallakury B.V.S. Furth P.A. Efatutazone, a PPARγ agonist, increases the spectrum of well-differentiated mammary cancer subtypes initiated by loss of full-length BRCA1 in association with p53 haploinsufficiency.Am J Pathol. 2013; 182: 1976-1985Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar is that the activation of PPARγ by its agonist reduced the incidence of non-invasive cancer and promoted more differentiated histology without affecting the incidence and histology of invasive cancers. These results clearly indicate a tumor suppressor function for PPARγ in breast cancer and confirm the complexity of PPARγ functions in carcinogenesis. Targeting the signaling pathways transduced by NRs is a valid approach for the treatment and prevention of different diseases including cancer. One well known example is the commonly prescribed tamoxifen, an ERα antagonist, for the treatment of ERα-positive breast cancers. As a crucial regulator of cell proliferation, differentiation, and apoptosis,11Sertznig P. Seifert M. Tilgen W. Reichrath J. Peroxisome proliferator-activated receptors (PPARs) and the human skin: importance of PPARs in skin physiology and dermatologic diseases.Am J Clin Dermatol. 2008; 9: 15-31Crossref PubMed Scopus (99) Google Scholar PPARγ has been evaluated as a target for therapeutic development, and agonists for PPARγ have been developed for the treatment of different diseases.2Han S. Roman J. Peroxisome proliferator-activated receptor gamma: a novel target for cancer therapeutics?.Anticancer Drugs. 2007; 18: 237-244Crossref PubMed Scopus (108) Google Scholar However, PPARγ appears to have contradicting functions in tumorigenesis, which is likely determined by the molecular contexts of cells. First of all, a number of studies have showed a suppressive function of PPARγ in cultured breast cancer cells, including both ER-positive (eg, MCF-7) and ER-negative cells (eg, MDA-MB-231). The suppressive activities include inhibition of cell proliferation, induction of apoptosis, and promotion of differentiation.12Kim K.Y. Cheon H.G. Antiangiogenic effect of rosiglitazone is mediated via peroxisome proliferator-activated receptor gamma-activated maxi-K channel opening in human umbilical vein endothelial cells.J Biol Chem. 2006; 281: 13503-13512Crossref PubMed Scopus (32) Google Scholar The effects have been detected in both ER-positive and ER-negative breast cancer cells, and the findings among different studies are generally consistent. However, findings in PPARγ functions from animal studies are less consistent and sometimes contradicting, which is somewhat parallel to the dual expression trends of PPARγ in human tumors. On one hand, there are plenty of animal studies showing a tumor suppressor function of PPARγ. For example, TZD suppresses the tumorigenesis of MCF-7 human breast cancer cells in nude mice,13Elstner E. Muller C. Koshizuka K. Williamson E.A. Park D. Asou H. Shintaku P. Said J.W. Heber D. Koeffler H.P. Ligands for peroxisome proliferator-activated receptorgamma and retinoic acid receptor inhibit growth and induce apoptosis of human breast cancer cells in vitro and in BNX mice.Proc Natl Acad Sci U S A. 1998; 95: 8806-8811Crossref PubMed Scopus (760) Google Scholar knockout of PPARγ increases tumor incidence and metastasis in DMBA-induced tumorigenesis,14Nicol C.J. Yoon M. Ward J.M. Yamashita M. Fukamachi K. Peters J.M. Gonzalez F.J. PPARgamma influences susceptibility to DMBA-induced mammary, ovarian and skin carcinogenesis.Carcinogenesis. 2004; 25: 1747-1755Crossref PubMed Scopus (105) Google Scholar and PPARγ agonist shows both tumor suppressive and chemoprotective effects on tumorigenesis induced by the combined treatment of excess hormone and the DMBA carcinogen.15Yin Y. Russell R.G. Dettin L.E. Bai R. Wei Z.L. Kozikowski A.P. Kopelovich L. Glazer R.I. Peroxisome proliferator-activated receptor delta and gamma agonists differentially alter tumor differentiation and progression during mammary carcinogenesis.Cancer Res. 2005; 65: 3950-3957Crossref PubMed Scopus (88) Google Scholar In addition, expression of the dominant-negative Pax8-PPARG fusion gene in mouse mammary epithelial cells, although not tumorigenic itself, makes cells highly susceptible to DMBA-induced tumorigenesis.16Yin Y. Yuan H. Zeng X. Kopelovich L. Glazer R.I. Inhibition of peroxisome proliferator-activated receptor gamma increases estrogen receptor-dependent tumor specification.Cancer Res. 2009; 69: 687-694Crossref PubMed Scopus (38) Google Scholar The paper by Nakles et al1Nakles R.E. Kallakury B.V.S. Furth P.A. Efatutazone, a PPARγ agonist, increases the spectrum of well-differentiated mammary cancer subtypes initiated by loss of full-length BRCA1 in association with p53 haploinsufficiency.Am J Pathol. 2013; 182: 1976-1985Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar adds to the list of studies. On the other hand, an oncogenic role has also been detected for PPARγ, although the mechanism for such an opposite function is not really understood. For example, overexpression of PPARγ increases the risk of mammary tumor in mice that are prone to developing the disease.17Saez E. Rosenfeld J. Livolsi A. Olson P. Lombardo E. Nelson M. Banayo E. Cardiff R.D. Izpisua-Belmonte J.C. Evans R.M. PPAR gamma signaling exacerbates mammary gland tumor development.Genes Dev. 2004; 18: 528-540Crossref PubMed Scopus (167) Google Scholar Using the MMTV-Her-2/neu transgenic mouse model of mammary tumorigenesis, Saez et al18Yee L.D. Young D.C. Rosol T.J. Vanbuskirk A.M. Clinton S.K. Dietary (n-3) polyunsaturated fatty acids inhibit HER-2/neu-induced breast cancer in mice independently of the PPARgamma ligand rosiglitazone.J Nutr. 2005; 135: 983-988PubMed Google Scholar found that PPARγ overexpression did not prevent, but instead greatly accelerated tumorigenesis, although bigenic tumors are more secretory and differentiated. Expression of a constitutively active form of PPARγ also accelerated mammary tumorigenesis in the transgenic MMTV-PyV mice, which are prone to mammary cancer development.17Saez E. Rosenfeld J. Livolsi A. Olson P. Lombardo E. Nelson M. Banayo E. Cardiff R.D. Izpisua-Belmonte J.C. Evans R.M. PPAR gamma signaling exacerbates mammary gland tumor development.Genes Dev. 2004; 18: 528-540Crossref PubMed Scopus (167) Google Scholar Contradicting findings have also been reported in other types of cancers including colon cancer.17Saez E. Rosenfeld J. Livolsi A. Olson P. Lombardo E. Nelson M. Banayo E. Cardiff R.D. Izpisua-Belmonte J.C. Evans R.M. PPAR gamma signaling exacerbates mammary gland tumor development.Genes Dev. 2004; 18: 528-540Crossref PubMed Scopus (167) Google Scholar Clinical studies have also been inconsistent for the effects of PPARγ agonists on human breast cancer. Use of PPARγ agonists TZD is associated with better survival for diabetics with HER2-positive breast cancer,19He X. Esteva F.J. Ensor J. Hortobagyi G.N. Lee M.H. Yeung S.C. Metformin and thiazolidinediones are associated with improved breast cancer-specific survival of diabetic women with HER2+ breast cancer.Ann Oncol. 2012; 23: 1771-1780Crossref PubMed Scopus (155) Google Scholar but patients with metastatic breast cancer do not appear to show any clinical benefits of TZD use.20Burstein H.J. Demetri G.D. Mueller E. Sarraf P. Spiegelman B.M. Winer E.P. Use of the peroxisome proliferator-activated receptor (PPAR) gamma ligand troglitazone as treatment for refractory breast cancer: a phase II study.Breast Cancer Res Treat. 2003; 79: 391-397Crossref PubMed Scopus (198) Google Scholar There are at least several possibilities for discrepancies in PPARγ function in breast cancer among different studies, and Nakles et al1Nakles R.E. Kallakury B.V.S. Furth P.A. Efatutazone, a PPARγ agonist, increases the spectrum of well-differentiated mammary cancer subtypes initiated by loss of full-length BRCA1 in association with p53 haploinsufficiency.Am J Pathol. 2013; 182: 1976-1985Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar provide some insight. Better understanding of how PPARγ functions and interacts with other signaling pathways should help clarify the issue, thereby improving the design and outcome of clinical trials. For example, if PPARγ is only relevant to more differentiated ER-positive breast cancer as suggested by Nakles et al1Nakles R.E. Kallakury B.V.S. Furth P.A. Efatutazone, a PPARγ agonist, increases the spectrum of well-differentiated mammary cancer subtypes initiated by loss of full-length BRCA1 in association with p53 haploinsufficiency.Am J Pathol. 2013; 182: 1976-1985Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar and other studies, it would not make sense to use advanced breast cancers, which are often metastatic and ER-negative, in a clinical trial for PPARγ agonists. One possibility for inconsistent functions of PPARγ is that PPARγ functions in a context-dependent manner. For example, certain molecular pathways need to be present or absent for PPARγ to function. Nakles et al1Nakles R.E. Kallakury B.V.S. Furth P.A. Efatutazone, a PPARγ agonist, increases the spectrum of well-differentiated mammary cancer subtypes initiated by loss of full-length BRCA1 in association with p53 haploinsufficiency.Am J Pathol. 2013; 182: 1976-1985Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar used mice that undergo a mammary epithelial cell targeted deletion of Brca1 in somatic cells coupled with germline Trp53 haplo-insufficiency. These mice provide a model that is relevant to the human disease because both genes are functionally inactivated in some human breast cancer. The findings of a tumor suppressor function for PPARγ thus suggest that breast cancers with abnormal BRCA1 and TP53 would respond to PPARγ agonists. There are reported links between PPARγ function and BRCA1 and TP53. For TP53, TZD rosiglitazone has been shown to increase the expression of TP53 and its effector p21 (WAF1/Cip1).21Bonofiglio D. Aquila S. Catalano S. Gabriele S. Belmonte M. Middea E. Qi H. Morelli C. Gentile M. Maggiolini M. Ando S. Peroxisome proliferator-activated receptor-gamma activates p53 gene promoter binding to the nuclear factor-kappaB sequence in human MCF7 breast cancer cells.Mol Endocrinol. 2006; 20: 3083-3092Crossref PubMed Scopus (84) Google Scholar In addition, mammary epithelial cells from mice with TP53 insufficiency undergo more frequent spontaneous immortalization, and treatment with rosiglitazone, another agonist of PPARγ, reduces the frequency of spontaneous immortalization.22Herbert B.S. Pearce V.P. Hynan L.S. LaRue D.M. Wright W.E. Kopelovich L. Shay J.W. A peroxisome proliferator-activated receptor-gamma agonist and the p53 rescue drug CP-31398 inhibit the spontaneous immortalization of breast epithelial cells.Cancer Res. 2003; 63: 1914-1919PubMed Google Scholar Taken together with Nakles et al,1Nakles R.E. Kallakury B.V.S. Furth P.A. Efatutazone, a PPARγ agonist, increases the spectrum of well-differentiated mammary cancer subtypes initiated by loss of full-length BRCA1 in association with p53 haploinsufficiency.Am J Pathol. 2013; 182: 1976-1985Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar it is likely that proper function of PPARγ needs functional TP53. If that be the case, efatutazone treatment could increase TP53 expression, which was not examined in the paper. A relevance of PPARγ to BRCA1 is also possible, as PPARγ agonists induce the expression of BRCA1 in both cultured cells and mammary tissues.23Subbaramaiah K. Howe L.R. Zhou X.K. Yang P. Hudis C.A. Kopelovich L. Dannenberg A.J. Pioglitazone, a PPARgamma agonist, suppresses CYP19 transcription: evidence for involvement of 15-hydroxyprostaglandin dehydrogenase and BRCA1.Cancer Prev Res (Phila). 2012; 5: 1183-1194Crossref Scopus (23) Google Scholar Another proliferation-related pathway suppressed by PPARγ agonist is Akt/PTEN, as TZDs increase PTEN expression in MCF-7 breast cancer cells and decrease Akt phosphorylation.24Kim K.Y. Kim S.S. Cheon H.G. Differential anti-proliferative actions of peroxisome proliferator-activated receptor-gamma agonists in MCF-7 breast cancer cells.Biochem Pharmacol. 2006; 72: 530-540Crossref PubMed Scopus (67) Google Scholar Consistently, interruption of PPARγ by expressing the PAX8/PPAR fusion gene reduces Pten expression and increases AKT activation in both normal and cancer cells.16Yin Y. Yuan H. Zeng X. Kopelovich L. Glazer R.I. Inhibition of peroxisome proliferator-activated receptor gamma increases estrogen receptor-dependent tumor specification.Cancer Res. 2009; 69: 687-694Crossref PubMed Scopus (38) Google Scholar Nakles et al1Nakles R.E. Kallakury B.V.S. Furth P.A. Efatutazone, a PPARγ agonist, increases the spectrum of well-differentiated mammary cancer subtypes initiated by loss of full-length BRCA1 in association with p53 haploinsufficiency.Am J Pathol. 2013; 182: 1976-1985Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar confirm that efatutazone decreased the expression of p-AKT without affecting the total level of AKT expression, although Pten expression was not evaluated in the model. There is evidence for PPARγ signaling to interact with other signaling pathways, including STAT5B, NF-κB, TGF-β, and Ras/MAPK.16Yin Y. Yuan H. Zeng X. Kopelovich L. Glazer R.I. Inhibition of peroxisome proliferator-activated receptor gamma increases estrogen receptor-dependent tumor specification.Cancer Res. 2009; 69: 687-694Crossref PubMed Scopus (38) Google Scholar Ligand activation of PPARγ has been shown to potentiate Wnt signaling in an in vivo model of mouse mammary tumorigenesis.17Saez E. Rosenfeld J. Livolsi A. Olson P. Lombardo E. Nelson M. Banayo E. Cardiff R.D. Izpisua-Belmonte J.C. Evans R.M. PPAR gamma signaling exacerbates mammary gland tumor development.Genes Dev. 2004; 18: 528-540Crossref PubMed Scopus (167) Google Scholar These pathways were not evaluated in the Nakles study,1Nakles R.E. Kallakury B.V.S. Furth P.A. Efatutazone, a PPARγ agonist, increases the spectrum of well-differentiated mammary cancer subtypes initiated by loss of full-length BRCA1 in association with p53 haploinsufficiency.Am J Pathol. 2013; 182: 1976-1985Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar so it is not clear whether the effect of efatutazone on tumorigenesis in the discussed paper is associated with any of these pathways. Improved understanding of molecular signatures associated with different effects of PPARγ agonists should help us to develop PPARγ-based therapies in the treatment and prevention of breast cancer. The connection with ER is another important aspect in the function of PPARγ signaling. In the Nakles study,1Nakles R.E. Kallakury B.V.S. Furth P.A. Efatutazone, a PPARγ agonist, increases the spectrum of well-differentiated mammary cancer subtypes initiated by loss of full-length BRCA1 in association with p53 haploinsufficiency.Am J Pathol. 2013; 182: 1976-1985Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar efatutazone treatment led to the formation of more differentiated ER-positive tumors, which suggests a positive association between PPARγ function and ER expression. On the other hand, inhibition of PPARγ function via expressing the dominant-negative Pax8-PPARγ fusion gene made DMBA-induced mouse mammary tumors also ER-positive, and subsequently highly responsive to the ER antagonist fulvestrant in tumor prevention.16Yin Y. Yuan H. Zeng X. Kopelovich L. Glazer R.I. Inhibition of peroxisome proliferator-activated receptor gamma increases estrogen receptor-dependent tumor specification.Cancer Res. 2009; 69: 687-694Crossref PubMed Scopus (38) Google Scholar Based on this study and Nakles et al,1Nakles R.E. Kallakury B.V.S. Furth P.A. Efatutazone, a PPARγ agonist, increases the spectrum of well-differentiated mammary cancer subtypes initiated by loss of full-length BRCA1 in association with p53 haploinsufficiency.Am J Pathol. 2013; 182: 1976-1985Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar it becomes interesting to know whether combined use of efatutazone and an ER antagonist has any additive or synergistic (or even neutralizing) effect on mammary tumorigenesis induced by Brca1 deficiency and Trp53 insufficiency. A direct connection between PPARγ function and ER transcription has also been reported, although in an opposite manner. In mouse mammary organ cultures, although DMBA-induced mammary alveolar lesions (MAL) were inhibited by either an agonist or an antagonist of PPARγ, it is the antagonist and not the agonist that induced ER and PR expression in the presence of estrogen.25Mehta R.G. Peng X. Roy S. Hawthorne M. Kalra A. Alimirah F. Mehta R.R. Kopelovich L. PPARgamma antagonist GW9662 induces functional estrogen receptor in mouse mammary organ culture: potential translational significance.Mol Cell Biochem. 2013; 372: 249-256Crossref PubMed Scopus (6) Google Scholar Further insights into the relationship between PPARγ signaling and ER signaling could lead to better intervention of breast cancer using a combined use of PPARγ agonists and ER antagonists. An interesting observation by Nakles et al1Nakles R.E. Kallakury B.V.S. Furth P.A. Efatutazone, a PPARγ agonist, increases the spectrum of well-differentiated mammary cancer subtypes initiated by loss of full-length BRCA1 in association with p53 haploinsufficiency.Am J Pathol. 2013; 182: 1976-1985Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar is that efatutazone lacks an effect on invasive tumors. It is possible that this group of cancers originated from cells with distinct molecular alterations. It is also possible, as the authors discuss, that invasive cancers come from efatutazone-resistant cancer or cancer progenitor cells that are not clinically well characterized. Although not addressed in the study, it would be interesting to compare invasive cancers to the non-invasive, more differentiated, and ER-positive cancers for the molecular pathways associated with PPARγ signaling. Molecular differences between the two groups of cancers should help clarify what molecular pathways and signatures are required or altered by PPARγ activation and what are specific to invasive cancers that are not responsive to PPARγ activation. Another outstanding question is how both enhanced and attenuated PPARγ activities induce ER-positive tumors in the mammary gland. As nuclear receptors, it is not impossible that PPARγ and ER have direct interactions. A speculation is that the pro-differentiation function of PPARγ restrains the pro-proliferative/tumorigenic function of ER via direct interaction, and the inactivation of PPARγ could thus release or enhance the pro-proliferative/tumorigenic function of ER, leading to the transformation of luminal cells that are already ER-positive to tumor cells that remain ER-positive. This possibility is worth testing in future studies. It is also possible that progenitor cells, which are ER-negative, have acquired tumor-initiating events while differentiating into ER-positive cells under the influence of pro-differentiation function of PPARγ, and eventually become fully transformed cells that are ER positive. Finally, efatutazone was administered at four month of age, which leaves several questions unaddressed. For example, could efatutazone treatment modify some early cancer or progenitor cells toward a more differentiated phenotype? Could early administration of efatutazone prevent the occurrence of the more differentiated ER-positive cancer? Is the effect of efatutazone reversible? In summary, the results produced by Nakles et al1Nakles R.E. Kallakury B.V.S. Furth P.A. Efatutazone, a PPARγ agonist, increases the spectrum of well-differentiated mammary cancer subtypes initiated by loss of full-length BRCA1 in association with p53 haploinsufficiency.Am J Pathol. 2013; 182: 1976-1985Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar have several implications: i) PPARγ activation indeed interferes with tumor development, ii) the tumor suppressor function of PPARγ is more likely associated with its pro-differentiation function, and iii) PPARγ activation is only effective in specific cells that could be at a specific stage of malignant transformation or have a distinct set of molecular alterations. Clarification of molecular basis for the different effects of efatutazone on tumor development and histology should help the development of PPARγ agonists as therapeutic and/or preventive reagents in breast cancer and other types of cancers.
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