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Molecular Cancer
Published in: Molecular Cancer 1/2008

Open Access 01-12-2008 | Research

Down-regulation of PPARgamma1 suppresses cell growth and induces apoptosis in MCF-7 breast cancer cells

Authors: Yekaterina Y Zaytseva, Xin Wang, R Chase Southard, Natalie K Wallis, Michael W Kilgore

Published in: Molecular Cancer | Issue 1/2008

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Abstract

Background

Peroxisome proliferator-activated receptor gamma (PPARγ) is a member of the nuclear hormone receptor superfamily and is highly expressed in many human tumors including breast cancer. PPARγ has been identified as a potential target for breast cancer therapy based on the fact that its activation by synthetic ligands affects the differentiation, proliferation, and apoptosis of cancer cells. However, the controversial nature of current studies and disappointing results from clinical trials raise questions about the contribution of PPARγ signaling in breast cancer development in the absence of stimulation by exogenous ligands. Recent reports from both in vitro and in vivo studies are inconsistent and suggest that endogenous activation of PPARγ plays a much more complex role in initiation and progression of cancer than previously thought.

Results

We have previously demonstrated that an increase in expression of PPARγ1 in MCF-7 breast cancer cells is driven by a tumor-specific promoter. Myc-associated zinc finger protein (MAZ) was identified as a transcriptional mediator of PPARγ1 expression in these cells. In this study, using RNA interference (RNAi) to inhibit PPARγ1 expression directly or via down-regulation of MAZ, we report for the first time that a decrease in PPARγ1 expression results in reduced cellular proliferation in MCF-7 breast cancer cells. Furthermore, we demonstrate that these changes in proliferation are associated with a significant decrease in cell transition from G1 to the S phase. Using a dominant-negative mutant of PPARγ1, Δ462, we confirmed that PPARγ1 acts as a pro-survival factor and showed that this phenomenon is not limited to MCF-7 cells. Finally, we demonstrate that down-regulation of PPARγ1 expression leads to an induction of apoptosis in MCF-7 cells, confirmed by analyzing Bcl-2 expression and PARP-1 cleavage.

Conclusion

Thus, these findings suggest that an increase in PPARγ1 signaling observed in breast cancer contributes to an imbalance between proliferation and apoptosis, and may be an important hallmark of breast tumorigenesis. The results presented here also warrant further investigation regarding the use of PPARγ ligands in patients who are predisposed or already diagnosed with breast cancer.
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Literature
1.
Cancer Facts & Figures 2007. 2007, Atlanta: American Cancer Society.
2.
Fajas L, Auboeuf D, Raspe E, Schoonjans K, Lefebvre AM, Saladin R, Najib J, Laville M, Fruchart JC, Deeb S, Vidal-Puig A, Flier J, Briggs MR, Staels B, Vidal H, Auwerx J: The organization, promoter analysis, and expression of the human PPARgamma gene. J Biol Chem. 1997, 272: 18779-18789. 10.1074/jbc.272.30.18779CrossRefPubMed
3.
Barak Y, Nelson MC, Ong ES, Jones YZ, Ruiz-Lozano P, Chien KR, Koder A, Evans RM: PPAR gamma is required for placental, cardiac, and adipose tissue development. Mol Cell. 1999, 4: 585-595. 10.1016/S1097-2765(00)80209-9CrossRefPubMed
4.
Barroso I, Gurnell M, Crowley VE, Agostini M, Schwabe JW, Soos MA, Maslen GL, Williams TD, Lewis H, Schafer AJ, Chatterjee VK, O'Rahilly S: Dominant negative mutations in human PPARgamma associated with severe insulin resistance, diabetes mellitus and hypertension. Nature. 1999, 402: 880-883.PubMed
5.
Kubota N, Terauchi Y, Miki H, Tamemoto H, Yamauchi T, Komeda K, Satoh S, Nakano R, Ishii C, Sugiyama T, Eto K, Tsubamoto Y, Okuno A, Murakami K, Sekihara H, Hasegawa G, Naito M, Toyoshima Y, Tanaka S, Shiota K, Kitamura T, Fujita T, Ezaki O, Aizawa S, Kadowaki T: PPAR gamma mediates high-fat diet-induced adipocyte hypertrophy and insulin resistance. Mol Cell. 1999, 4: 597-609. 10.1016/S1097-2765(00)80210-5CrossRefPubMed
6.
Mukherjee R, Jow L, Croston GE, Paterniti Jr: Identification, characterization, and tissue distribution of human peroxisome proliferator-activated receptor (PPAR) isoforms PPARgamma2 versus PPARgamma1 and activation with retinoid X receptor agonists and antagonists. J Biol Chem. 1997, 272: 8071-8076. 10.1074/jbc.272.4.2346CrossRefPubMed
7.
Nwankwo JO, Robbins ME: Peroxisome proliferator-activated receptor- gamma expression in human malignant and normal brain, breast and prostate-derived cells. Prostaglandins Leukot Essent Fatty Acids. 2001, 64: 241-245. 10.1054/plef.2001.0266CrossRefPubMed
8.
Issemann I, Prince RA, Tugwood JD, Green S: The peroxisome proliferator-activated receptor:retinoid X receptor heterodimer is activated by fatty acids and fibrate hypolipidaemic drugs. J Mol Endocrinol. 1993, 11: 37-47. 10.1677/jme.0.0110037CrossRefPubMed
9.
Keller H, Dreyer C, Medin J, Mahfoudi A, Ozato K, Wahli W: Fatty acids and retinoids control lipid metabolism through activation of peroxisome proliferator-activated receptor-retinoid X receptor heterodimers. Proc Natl Acad Sci USA. 1993, 90: 2160-2164. 10.1073/pnas.90.6.2160PubMedCentralCrossRefPubMed
10.
Thoennes SR, Tate PL, Price TM, Kilgore MW: Differential transcriptional activation of peroxisome proliferator-activated receptor gamma by omega-3 and omega-6 fatty acids in MCF-7 cells. Mol Cell Endocrinol. 2000, 160: 67-73. 10.1016/S0303-7207(99)00254-3CrossRefPubMed
11.
Kliewer SA, Lenhard JM, Willson TM, Patel I, Morris DC, Lehmann JM: A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor gamma and promotes adipocyte differentiation. Cell. 1995, 83: 813-819. 10.1016/0092-8674(95)90194-9CrossRefPubMed
12.
Berger J, Bailey P, Biswas C, Cullinan CA, Doebber TW, Hayes NS, Saperstein R, Smith RG, Leibowitz MD: Thiazolidinediones produce a conformational change in peroxisomal proliferator-activated receptor-gamma: binding and activation correlate with antidiabetic actions in db/db mice. Endocrinology. 1996, 137: 4189-4195. 10.1210/en.137.10.4189PubMed
13.
Lehmann JM, Moore LB, Smith-Oliver TA, Wilkison WO, Willson TM, Kliewer SA: An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J Biol Chem. 1995, 270: 12953-12956. 10.1074/jbc.270.50.30221CrossRefPubMed
14.
Lehmann JM, Lenhard JM, Oliver BB, Ringold GM, Kliewer SA: Peroxisome proliferator-activated receptors alpha and gamma are activated by indomethacin and other non-steroidal anti-inflammatory drugs. J Biol Chem. 1997, 272: 3406-3410. 10.1074/jbc.272.6.3406CrossRefPubMed
15.
Houseknecht KL, Cole BM, Steele PJ: Peroxisome proliferator-activated receptor gamma (PPARgamma) and its ligands: a review. Domest Anim Endocrinol. 2002, 22: 1-23. 10.1016/S0739-7240(01)00117-5CrossRefPubMed
16.
17.
Mueller E, Smith M, Sarraf P, Kroll T, Aiyer A, Kaufman DS, Oh W, Demetri G, Figg WD, Zhou XP, Eng C, Spiegelman BM, Kantoff PW: Effects of ligand activation of peroxisome proliferator-activated receptor gamma in human prostate cancer. Proc Natl Acad Sci USA. 2000, 97: 10990-10995. 10.1073/pnas.180329197PubMedCentralCrossRefPubMed
18.
Shen D, Deng C, Zhang M: Peroxisome proliferator-activated receptor gamma agonists inhibit the proliferation and invasion of human colon cancer cells. Postgrad Med J. 2007, 83: 414-419. 10.1136/pmj.2006.052761PubMedCentralCrossRefPubMed
19.
Kim KY, Kim SS, Cheon HG: Differential anti-proliferative actions of peroxisome proliferator-activated receptor-gamma agonists in MCF-7 breast cancer cells. Biochem Pharmacol. 2006, 72: 530-540. 10.1016/j.bcp.2006.05.009CrossRefPubMed
20.
Mehta RG, Williamson E, Patel MK, Koeffler HP: A ligand of peroxisome proliferator-activated receptor gamma, retinoids, and prevention of preneoplastic mammary lesions. J Natl Cancer Inst. 2000, 92: 418-423. 10.1093/jnci/92.5.418CrossRefPubMed
21.
Mueller E, Sarraf P, Tontonoz P, Evans RM, Martin KJ, Zhang M, Fletcher C, Singer S, Spiegelman BM: Terminal differentiation of human breast cancer through PPAR gamma. Mol Cell. 1998, 1: 465-470. 10.1016/S1097-2765(00)80047-7CrossRefPubMed
22.
Yin F, Wakino S, Liu Z, Kim S, Hsueh WA, Collins AR, Van Herle AJ, Law RE: Troglitazone inhibits growth of MCF-7 breast carcinoma cells by targeting G1 cell cycle regulators. Biochem Biophys Res Commun. 2001, 286: 916-922. 10.1006/bbrc.2001.5491CrossRefPubMed
23.
Liu H, Zang C, Fenner MH, Possinger K, Elstner E: PPARgamma ligands and ATRA inhibit the invasion of human breast cancer cells in vitro. Breast Cancer Res Treat. 2003, 79: 63-74. 10.1023/A:1023366117157CrossRefPubMed
24.
Panigrahy D, Huang S, Kieran MW, Kaipainen A: PPARgamma as a therapeutic target for tumor angiogenesis and metastasis. Cancer Biol Ther. 2005, 4: 687-693.CrossRefPubMed
25.
Abe A, Kiriyama Y, Hirano M, Miura T, Kamiya H, Harashima H, Tokumitsu Y: Troglitazone suppresses cell growth of KU812 cells independently of PPARgamma. Eur J Pharmacol. 2002, 436: 7-13. 10.1016/S0014-2999(01)01577-1CrossRefPubMed
26.
Lecomte J, Flament S, Salamone S, Boisbrun M, Mazerbourg S, Chapleur Y, Grillier-Vuissoz I: Disruption of ERalpha signalling pathway by PPARgamma agonists: evidences of PPARgamma-independent events in two hormone-dependent breast cancer cell lines. Breast Cancer Res Treat. 2008.
27.
Talbert DR, Allred CD, Zaytseva YY, Kilgore MW: Transactivation of ERalpha by Rosiglitazone induces proliferation in breast cancer cells. Breast Cancer Res Treat. 2008, 108: 23-33. 10.1007/s10549-007-9575-yCrossRefPubMed
28.
Burton JD, Goldenberg DM, Blumenthal RD: Potential of peroxisome proliferator-activated receptor gamma antagonist compounds as therapeutic agents for a wide range of cancer types. PPAR Res. 2008, 2008: 494161-PubMedCentralCrossRefPubMed
29.
Elstner E, Muller C, Koshizuka K, Williamson EA, Park D, Asou H, Shintaku P, Said JW, Heber D, Koeffler HP: 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 USA. 1998, 95: 8806-8811. 10.1073/pnas.95.15.8806PubMedCentralCrossRefPubMed
30.
Lefebvre AM, Chen I, Desreumaux P, Najib J, Fruchart JC, Geboes K, Briggs M, Heyman R, Auwerx J: Activation of the peroxisome proliferator-activated receptor gamma promotes the development of colon tumors in C57BL/6J-APCMin/+ mice. Nat Med. 1998, 4: 1053-1057. 10.1038/2036CrossRefPubMed
31.
Saez E, Rosenfeld J, Livolsi A, Olson P, Lombardo E, Nelson M, Banayo E, Cardiff RD, Izpisua-Belmonte JC, Evans RM: PPAR gamma signaling exacerbates mammary gland tumor development. Genes Dev. 2004, 18: 528-540. 10.1101/gad.1167804PubMedCentralCrossRefPubMed
32.
Cui Y, Miyoshi K, Claudio E, Siebenlist UK, Gonzalez FJ, Flaws J, Wagner KU, Hennighausen L: Loss of the peroxisome proliferation-activated receptor gamma (PPARgamma) does not affect mammary development and propensity for tumor formation but leads to reduced fertility. J Biol Chem. 2002, 277: 17830-17835. 10.1074/jbc.M200186200CrossRefPubMed
33.
Wang X, Southard RC, Kilgore MW: The increased expression of peroxisome proliferator-activated receptor-gamma1 in human breast cancer is mediated by selective promoter usage. Cancer Res. 2004, 64: 5592-5596. 10.1158/0008-5472.CAN-04-0043CrossRefPubMed
34.
Allred CD, Kilgore MW: Selective activation of PPARgamma in breast, colon, and lung cancer cell lines. Mol Cell Endocrinol. 2005, 235: 21-29. 10.1016/j.mce.2005.02.003CrossRefPubMed
35.
Wang T, Xu J, Yu X, Yang R, Han ZC: Peroxisome proliferator-activated receptor gamma in malignant diseases. Crit Rev Oncol Hematol. 2006, 58: 1-14. 10.1016/j.critrevonc.2005.08.011CrossRefPubMed
36.
Yee LD, Sabourin CL, Liu L, Li HM, Smith PJ, Seewaldt V, Kniss DA: Peroxisome proliferator-activated receptor gamma activation in human breast cancer. Int J Oncol. 1999, 15: 967-973.PubMed
37.
Wang X, Southard RC, Allred CD, Talbert DR, Wilson ME, Kilgore MW: MAZ drives tumor-specific expression of PPAR gamma 1 in breast cancer cells. Breast Cancer Res Treat. 2007, 111 (1): 103-111. 10.1007/s10549-007-9765-7PubMedCentralCrossRefPubMed
38.
Song J, Murakami H, Tsutsui H, Tang X, Matsumura M, Itakura K, Kanazawa I, Sun K, Yokoyama KK: Genomic organization and expression of a human gene for Myc-associated zinc finger protein (MAZ). J Biol Chem. 1998, 273: 20603-20614. 10.1074/jbc.273.32.20603CrossRefPubMed
39.
Spiegelman BM: PPAR-gamma: adipogenic regulator and thiazolidinedione receptor. Diabetes. 1998, 47: 507-514. 10.2337/diabetes.47.4.507CrossRefPubMed
40.
Huang Z: Bcl-2 family proteins as targets for anticancer drug design. Oncogene. 2000, 19: 6627-6631. 10.1038/sj.onc.1204087CrossRefPubMed
41.
Soldani C, Lazze MC, Bottone MG, Tognon G, Biggiogera M, Pellicciari CE, Scovassi AI: Poly(ADP-ribose) polymerase cleavage during apoptosis: when and where?. Exp Cell Res. 2001, 269: 193-201. 10.1006/excr.2001.5293CrossRefPubMed
42.
Kilgore MW, Tate PL, Rai S, Sengoku E, Price TM: MCF-7 and T47D human breast cancer cells contain a functional peroxisomal response. Mol Cell Endocrinol. 1997, 129: 229-235. 10.1016/S0303-7207(97)04057-4CrossRefPubMed
43.
Suzuki T, Hayashi S, Miki Y, Nakamura Y, Moriya T, Sugawara A, Ishida T, Ohuchi N, Sasano H: Peroxisome proliferator-activated receptor gamma in human breast carcinoma: a modulator of estrogenic actions. Endocr Relat Cancer. 2006, 13: 233-250. 10.1677/erc.1.01075CrossRefPubMed
44.
Clay CE, Monjazeb A, Thorburn J, Chilton FH, High KP: 15-Deoxy-delta12, 14-prostaglandin J2-induced apoptosis does not require PPARgamma in breast cancer cells. J Lipid Res. 2002, 43: 1818-1828. 10.1194/jlr.M200224-JLR200CrossRefPubMed
45.
Huang JW, Shiau CW, Yang YT, Kulp SK, Chen KF, Brueggemeier RW, Shapiro CL, Chen CS: Peroxisome proliferator-activated receptor gamma-independent ablation of cyclin D1 by thiazolidinediones and their derivatives in breast cancer cells. Mol Pharmacol. 2005, 67: 1342-1348. 10.1124/mol.104.007732CrossRefPubMed
46.
Clay CE, Namen AM, Atsumi G, Trimboli AJ, Fonteh AN, High KP, Chilton FH: Magnitude of peroxisome proliferator-activated receptor-gamma activation is associated with important and seemingly opposite biological responses in breast cancer cells. J Investig Med. 2001, 49: 413-420. 10.2310/6650.2001.33786CrossRefPubMed
47.
Seargent JM, Yates EA, Gill JH: GW a potent antagonist of PPARgamma, inhibits growth of breast tumour cells and promotes the anticancer effects of the PPARgamma agonist rosiglitazone, independently of PPARgamma activation. Br J Pharmacol. 9662, 143: 933-937. 10.1038/sj.bjp.0705973. 10.1038/sj.bjp.0705973CrossRef
48.
Letai AG: Diagnosing and exploiting cancer's addiction to blocks in apoptosis. Nat Rev Cancer. 2008, 8: 121-132. 10.1038/nrc2297CrossRefPubMed
Metadata
Title
Down-regulation of PPARgamma1 suppresses cell growth and induces apoptosis in MCF-7 breast cancer cells
Authors
Yekaterina Y Zaytseva
Xin Wang
R Chase Southard
Natalie K Wallis
Michael W Kilgore
Publication date
01-12-2008
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2008
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/1476-4598-7-90

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