Fine-tuning the lipogenic/lipolytic balance to optimize the metabolic requirements of cancer cell growth: Molecular mechanisms and therapeutic perspectives

Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids

Volumn 1801, Issue 3, 2010, Pages 381-391

  Menendez, Javier A ^a  

^a HOSPITAL JOSEP TRUETA   (Spain)

Author keywords

Cancer; Fatty Acid Synthase; HER2; Lipogenesis; Lipolysis; PPAR

Indexed keywords

FATTY ACID SYNTHASE; PALMITIC ACID; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA;

AMPLICON; BIOGENESIS; BREAST CANCER; CANCER CELL; CANCER GROWTH; CATALYSIS; CELL PROLIFERATION; CELL SURVIVAL; GENE OVEREXPRESSION; HUMAN; IMMUNOHISTOCHEMISTRY; LIPID METABOLISM; LIPID STORAGE; LIPOGENESIS; LIPOLYSIS; ONCOGENE NEU; PHENOTYPE; PRIORITY JOURNAL; REVIEW; UPREGULATION;

CELL GROWTH PROCESSES; DIETARY FATS; FATTY ACID SYNTHETASE COMPLEX; HUMANS; LIPOGENESIS; LIPOLYSIS; NEOPLASMS; PPAR GAMMA; RECEPTOR, ERBB-2; SIGNAL TRANSDUCTION;

EID: 76049105429     PISSN: 13881981     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bbalip.2009.09.005     Document Type: Review

References (151)

1. Kuhajda F.P. Fatty-acid synthase and human cancer: new perspectives on its role in tumor biology. Nutrition 16 (2000) 202-208
2. Menendez J.A., and Lupu R. Fatty acid synthase-catalyzed de novo fatty acid biosynthesis: from anabolic-energy-storage pathway in normal tissues to jack-of-all-trades in cancer cells. Arch. Immunol. Ther. Exp. (Warsz) 52 (2004) 414-426
3. Menendez J.A., and Lupu R. Oncogenic properties of the endogenous fatty acid metabolism: molecular pathology of fatty acid synthase in cancer cells. Curr. Opin. Clin. Nutr. Metab. Care 9 (2006) 346-357
4. Menendez J.A., Lupu R., and Colomer R. Targeting fatty acid synthase: potential for therapeutic intervention in her-2/neu-overexpressing breast cancer. Drug News Perspect. 18 (2005) 375-385
5. Kuhajda F.P. Fatty acid synthase and cancer: new application of an old pathway. Cancer Res. 66 (2006) 5977-5980
6. Lupu R., and Menendez J.A. Targeting fatty acid synthase in breast and endometrial cancer: an alternative to selective estrogen receptor modulators?. Endocrinology 147 (2006) 4056-4066
7. Menendez J.A., and Lupu R. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat. Rev., Cancer 7 (2007) 763-777
8. Menendez J.A., Vazquez-Martin A., Ortega F.J., and Fernandez-Real J.M. Fatty acid synthase: association with insulin resistance, type 2 diabetes, and cancer. Clin. Chem. 55 (2009) 425-438
9. Baron A., Migita T., Tang D., and Loda M. Fatty acid synthase: a metabolic oncogene in prostate cancer?. J. Cell. Biochem. 91 (2004) 47-53
10. Graner E., Tang D., Rossi S., Baron A., Migita T., Weinstein L.J., Lechpammer M., Huesken D., Zimmermann J., Signoretti S., and Loda M. The isopeptidase USP2a regulates the stability of fatty acid synthase in prostate cancer. Cancer Cell 5 (2004) 253-261
11. Menendez J.A., Decker J.P., and Lupu R. In support of fatty acid synthase (FAS) as a metabolic oncogene: extracellular acidosis acts in an epigenetic fashion activating FAS gene expression in cancer cells. J. Cell. Biochem. 94 (2005) 1-4
12. Menendez J.A., Colomer R., and Lupu R. Why does tumor-associated fatty acid synthase (oncogenic antigen-519) ignore dietary fatty acids?. Med. Hypotheses 64 (2005) 342-349
13. Menendez J.A., Vellon L., Oza B.P., and Lupu R. Does endogenous fatty acid metabolism allow cancer cells to sense hypoxia and mediate hypoxic vasodilatation? Characterization of a novel molecular connection between fatty acid synthase (FAS) and hypoxia-inducible factor-1alpha (HIF-1alpha)-related expression of vascular endothelial growth factor (VEGF) in cancer cells overexpressing her-2/neu oncogene. J. Cell. Biochem. 94 (2005) 857-863
14. Priolo C., Tang D., Brahamandan M., Benassi B., Sicinska E., Ogino S., Farsetti A., Porrello A., Finn S., Zimmermann J., Febbo P., and Loda M. The isopeptidase USP2a protects human prostate cancer from apoptosis. Cancer Res 66 (2006) 8625-8632
15. Di Vizio D., Sotgia F., Williams T.M., Hassan G.S., Capozza F., Frank P.G., Pestell R.G., Loda M., Freeman M.R., and Lisanti M.P. Caveolin-1 is required for the upregulation of fatty acid synthase (FASN), a tumor promoter, during prostate cancer progression. Cancer Biol. Ther. 6 (2007) 1263-1268
16. Vazquez-Martin A., Colomer R., Brunet J., Lupu R., and Menendez J.A. Overexpression of fatty acid synthase gene activates HER1/HER2 tyrosine kinase receptors in human breast epithelial cells. Cell Prolif. 41 (2008) 59-85
17. Fiorentino M., Zadra G., Palescandolo E., Fedele G., Bailey D., Fiore C., Nguyen P.L., Migita T., Zamponi R., Di Vizio D., Priolo C., Sharma C., Xie W., Hemler M.E., Mucci L., Giovannucci E., Finn S., and Loda M. Overexpression of fatty acid synthase is associated with palmitoylation of Wnt1 and cytoplasmic stabilization of beta-catenin in prostate cancer. Lab. Invest. 88 (2008) 1340-1348
18. Migita T., Ruiz S., Fornari A., Fiorentino M., Priolo C., Zadra G., Inazuka F., Grisanzio C., Palescandolo E., Shin E., Fiore C., Xie W., Kung A.L., Febbo P.G., Subramanian A., Mucci L., Ma J., Signoretti S., Stampfer M., Hahn W.C., Finn S., and Loda M. Fatty acid synthase: a metabolic enzyme and candidate oncogene in prostate cancer. J. Natl. Cancer Inst. 101 (2009) 519-532
19. Kumar-Sinha C., Ignatoski K.W., Lippman M.E., Ethier S.P., and Chinnaiyan A.M. Transcriptome analysis of HER2 reveals a molecular connection to fatty acid synthesis. Cancer Res. 63 (2003) 132-139
20. Menendez J.A., Ropero S., Mehmi I., Atlas E., Colomer R., and Lupu R. Overexpression and hyperactivity of breast cancer-associated fatty acid synthase (oncogenic antigen-519) is insensitive to normal arachidonic fatty acid-induced suppression in lipogenic tissues but it is selectively inhibited by tumoricidal alpha-linolenic and gamma-linolenic fatty acids: a novel mechanism by which dietary fat can alter mammary tumorigenesis. Int. J. Oncol. 24 (2004) 1369-1383
21. Menendez J.A., Mehmi I., Verma V.A., Teng P.K., and Lupu R. Pharmacological inhibition of fatty acid synthase (FAS): a novel therapeutic approach for breast cancer chemoprevention through its ability to suppress Her-2/neu (erbB-2) oncogene-induced malignant transformation. Mol. Carcinog. 41 (2004) 164-178
22. Alli P.M., Pinn M.L., Jaffee E.M., McFadden J.M., and Kuhajda F.P. Fatty acid synthase inhibitors are chemopreventive for mammary cancer in neu-N transgenic mice. Oncogene 24 (2005) 39-46
23. Yoon S., Lee M.Y., Park S.W., Moon J.S., Koh Y.K., Ahn Y.H., Park B.W., and Kim K.S. Up-regulation of acetyl-CoA carboxylase alpha and fatty acid synthase by human epidermal growth factor receptor 2 at the translational level in breast cancer cells. J. Biol. Chem. 282 (2007) 26122-26131
24. Chiang C.T., Way T.D., Tsai S.J., and Lin J.K. Diosgenin, a naturally occurring steroid, suppresses fatty acid synthase expression in HER2-overexpressing breast cancer cells through modulating Akt, mTOR and JNK phosphorylation. FEBS Lett. 581 (2007) 5735-5742
25. Grunt T.W., Wagner R., Grusch M., Berger W., Singer C.F., Marian B., Zielinski C.C., and Lupu R. Interaction between fatty acid synthase- and ErbB-systems in ovarian cancer cells. Biochem. Biophys. Res. Commun. 385 (2009) 454-459
26. Menendez J.A., Oza B.P., Atlas E., Verma V.A., Mehmi I., and Lupu R. Inhibition of tumor-associated fatty acid synthase activity antagonizes estradiol- and tamoxifen-induced agonist transactivation of estrogen receptor (ER) in human endometrial adenocarcinoma cells. Oncogene 23 (2004) 4945-4958
27. Menendez J.A., Mehmi I., Atlas E., Colomer R., and Lupu R. Novel signaling molecules implicated in tumor-associated fatty acid synthase-dependent breast cancer cell proliferation and survival: role of exogenous dietary fatty acids, p53-p21WAF1/CIP1, ERK1/2 MAPK, p27KIP1, BRCA1, and NF-kappaB. Int. J. Oncol. 24 (2004) 591-608
28. Menendez J.A., Lupu R., and Colomer R. Inhibition of tumor-associated fatty acid synthase hyperactivity induces synergistic chemosensitization of HER-2/neu-overexpressing human breast cancer cells to docetaxel (taxotere). Breast Cancer Res. Treat. 84 (2004) 183-195
29. Menendez J.A., Colomer R., and Lupu R. Inhibition of tumor-associated fatty acid synthase activity enhances vinorelbine (Navelbine)-induced cytotoxicity and apoptotic cell death in human breast cancer cells. Oncol. Rep. 12 (2004) 411-422
30. Menendez J.A., and Lupu R. RNA interference-mediated silencing of the p53 tumor-suppressor protein drastically increases apoptosis after inhibition of endogenous fatty acid metabolism in breast cancer cells. Int. J. Mol. Med. 15 (2005) 33-40
31. Menendez J.A., Vellon L., Colomer R., and Lupu R. Pharmacological and small interference RNA-mediated inhibition of breast cancer-associated fatty acid synthase (oncogenic antigen-519) synergistically enhances Taxol (paclitaxel)-induced cytotoxicity. Int. J. Cancer 115 (2005) 19-35
32. Lupu R., and Menendez J.A. Pharmacological inhibitors of Fatty Acid Synthase (FASN)-catalyzed endogenous fatty acid biogenesis: a new family of anti-cancer agents?. Curr. Pharm. Biotechnol. 7 (2006) 483-493
33. Vazquez-Martin A., Ropero S., Brunet J., Colomer R., and Menendez J.A. Inhibition of Fatty Acid Synthase (FASN) synergistically enhances the efficacy of 5-fluorouracil in breast carcinoma cells. Oncol. Rep. 18 (2007) 973-980
34. Carvalho M.A., Zecchin K.G., Seguin F., Bastos D.C., Agostini M., Rangel A.L., Veiga S.S., Raposo H.F., Oliveira H.C., Loda M., Coletta R.D., and Graner E. Fatty acid synthase inhibition with Orlistat promotes apoptosis and reduces cell growth and lymph node metastasis in a mouse melanoma model. Int. J. Cancer 123 (2008) 2557-2565
35. Liu H., Liu Y., and Zhang J.T. A new mechanism of drug resistance in breast cancer cells: fatty acid synthase overexpression-mediated palmitate overproduction. Mol. Cancer Ther. 7 (2008) 263-270
36. Horiguchi A., Asano T., Asano T., Ito K., Sumitomo M., and Hayakawa M. Pharmacological inhibitor of fatty acid synthase suppresses growth and invasiveness of renal cancer cells. J. Urol. 180 (2008) 729-736
37. Furuta E., Pai S.K., Zhan R., Bandyopadhyay S., Watabe M., Mo Y.Y., Hirota S., Hosobe S., Tsukada T., Miura K., Kamada S., Saito K., Iiizumi M., Liu W., Ericsson J., and Watabe K. Fatty acid synthase gene is up-regulated by hypoxia via activation of Akt and sterol regulatory element binding protein-1. Cancer Res. 68 (2008) 1003-1011
38. Menendez J.A., Vellon L., Mehmi I., Oza B.P., Ropero S., Colomer R., and Lupu R. Inhibition of fatty acid synthase (FAS) suppresses HER2/neu (erbB-2) oncogene overexpression in cancer cells. Proc. Natl. Acad. Sci. U. S. A. 101 (2004) 10715-10720
39. Menendez J.A., Vellon L., and Lupu R. Targeting fatty acid synthase-driven lipid rafts: a novel strategy to overcome trastuzumab resistance in breast cancer cells. Med. Hypotheses 64 (2005) 997-1001
40. Menendez J.A., Vellon L., and Lupu R. Orlistat: from antiobesity drug to anticancer agent in Her-2/neu (erbB-2)-overexpressing gastrointestinal tumors?. Exp. Biol. Med. (Maywood). 230 (2005) 151-154
41. Menendez J.A., Vellon L., and Lupu R. Antitumoral actions of the anti-obesity drug orlistat (Xenical™) in breast cancer cells: blockade of cell cycle progression, promotion of apoptotic cell death and PEA3-mediated transcriptional repression of Her2/neu (erbB-2) oncogene. Ann. Oncol. 16 (2005) 1253-1267
42. Menendez J.A., Vellon L., and Lupu R. The antiobesity drug Orlistat induces cytotoxic effects, suppresses Her-2/neu (erbB-2) oncogene overexpression, and synergistically interacts with trastuzumab (Herceptin) in chemoresistant ovarian cancer cells. Int. J. Gynecol. Cancer 16 (2006) 219-221
43. Vazquez-Martin A., Colomer R., Brunet J., and Menendez J.A. Pharmacological blockade of fatty acid synthase (FASN) reverses acquired autoresistance to trastuzumab (Herceptin by transcriptionally inhibiting 'HER2 super-expression' occurring in high-dose trastuzumab-conditioned SKBR3/Tzb100 breast cancer cells. Int. J. Oncol. 31 (2007) 769-776
44. Hardy S., Langelier Y., and Prentki M. Oleate activates phosphatidylinositol 3-kinase and promotes proliferation and reduces apoptosis of MDA-MB-231 breast cancer cells, whereas palmitate has opposite effects. Cancer Res. 60 (2000) 6353-6358
45. Listenberger L.L., and Schaffer J.E. Mechanisms of lipoapoptosis: implications for human heart disease. Trends Cardiovasc. Med. 12 (2002) 134-138
46. Hardy S., El-Assaad W., Przybytkowski E., Joly E., Prentki M., and Langelier Y. Saturated fatty acid-induced apoptosis in MDA-MB-231 breast cancer cells. A role for cardiolipin. J. Biol. Chem. 278 (2003) 31861-31870
47. Schaffer J.E. Lipotoxicity: when tissues overeat. Curr. Opin. Lipidol. 14 (2003) 281-287
48. Listenberger L.L., Han X., Lewis S.E., Cases S., Farese R.V., Ory D.S., and Schaffer J.E. Triglyceride accumulation protects against fatty acid-induced lipotoxicity. Proc. Natl. Acad. Sci. U. S. A. 100 (2003) 3077-3082
49. Brookheart R.T., Michel C.I., and Schaffer J.E. As a matter of fat. Cell Metab. 10 (2009) 9-12
50. Desvergne B., and Wahli W. Peroxisome proliferators-activated receptors: nuclear control of metabolism. Endocr. Rev. 20 (1999) 649-688
51. Slamon D.J., Clark G.M., Wrong S.G., Levin W.J., Ullrich A., and McGuire W.L. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235 (1987) 177-182
52. Isola J., Chu L., DeVries S., Matsumura K., Chew K., Ljung B.M., and Waldman F.M. Genetic alterations in ERBB2-amplified breast carcinomas. Clin. Cancer Res. 5 (1999) 4140-4145
53. Pegram M.D., Konecny G., and Slamon D.J. The molecular and cellular biology of HER2/neu gene amplification/overexpression and the clinical development of herceptin (trastuzumab) therapy for breast cancer. Cancer Treat. Res. 103 (2000) 57-75
54. Yarden Y., and Sliwkowski M.X. Untangling the ErbB signalling network. Nat. Rev., Mol. Cell Biol. 2 (2001) 127-137
55. Zhang D.H., Salto-Tellez M., Do E., Putti T.C., and Koay E.S.C. Evaluation of HER-2/neu oncogene status in breast tumors on tissue microarrays. Hum. Pathol. 34 (2003) 362-368
56. Bertucci F., Borie N., Ginestier C., Groulet A., Charafe-Jauffret E., Adélaïde J., Geneix J., Bachelart L., Finetti P., Koki A., Hermitte F., Hassoun J., Debono S., Viens P., Fert V., Jacquemier J., and Birnbaum D. Identification and validation of an ERBB2 gene expression signature in breast cancers. Oncogene 23 (2004) 2564-2575
57. Nahta R., Yu D., Hung M.C., Hortobagyi G.N., and Esteva F.J. Mechanisms of disease: understanding resistance to HER2-targeted therapy in human breast cancer. Nat. Clin. Pract. Oncol. 3 (2006) 269-280
58. Lan K.H., Lu C.H., and Yu D. Mechanisms of trastuzumab resistance and their clinical implications. Ann. N.Y. Acad. Sci. 1059 (2005) 70-75
59. Pietras R.J., Arboleda J., Reese D.M., Wongvipat N., Pegram M.D., Ramos L., Gorman C.M., Parker M.G., Sliwkowski M.X., and Slamon D.J. HER-2 tyrosine kinase pathway targets estrogen receptor and promotes hormone-independent growth in human breast cancer cells. Oncogene 10 (1995) 2435-2446
60. Alaoui-Jamali M.A., Paterson J., Al Moustafa A.E., and Yen L. The role of ErbB2 tyrosine kinase receptor in cellular intrinsic chemoresistance: mechanisms and implications. Biochem. Cell Biol. 75 (1997) 315-325
61. Yarden Y. Biology of HER2 and its importance in breast cancer. Oncology 61 (2001) 1-13
62. Marmor M.D., Skaria K.B., and Yarden Y. Signal transduction and oncogenesis by ErbB/HER receptors. Int. J. Radiat. Oncol. Biol. Phys. 58 (2004) 903-913
63. Citri A., and Yarden Y. EGF-ERBB signalling: towards the systems level. Nat. Rev., Mol. Cell Biol. 7 (2006) 505-516
64. Zhang D., Tai L.K., Wong L.L., Chiu L.L., Sethi S.K., and Koay E.S. Proteomic study reveals that proteins involved in metabolic and detoxification pathways are highly expressed in HER-2/neu-positive breast cancer. Mol. Cell Proteomics. 4 (2005) 1686-1696
65. Vincent-Salomon A., Lucchesi C., Gruel N., Raynal V., Pierron G., Goudefroye R., Reyal F., Radvanyi F., Salmon R., Thiery J.P., Sastre-Garau X., Sigal-Zafrani B., Fourquet A., and Delattre O. Breast cancer study group of the Institut Curie, Integrated genomic and transcriptomic analysis of ductal carcinoma in situ of the breast, Clin. Cancer Res. 14 (2008) 1956-1965
66. Eberlé D., Hegarty B., Bossard P., Ferré P., and Foufelle F. SREBP transcription factors: master regulators of lipid homeostasis. Biochimie 86 (2004) 839-848
67. Dentin R., Girard J., and Postic C. Carbohydrate responsive element binding protein (ChREBP) and sterol regulatory element binding protein-1c (SREBP-1c): two key regulators of glucose metabolism and lipid synthesis in liver. Biochimie 87 (2005) 81-86
68. Raghow R., Yellaturu C., Deng X., Park E.A., and Elam M.B. SREBPs: the crossroads of physiological and pathological lipid homeostasis. Trends Endocrinol. Metab. 19 (2008) 65-73
69. Li J.N., Mahmoud M.A., Han W.F., Ripple M., and Pizer E.S. Sterol regulatory element-binding protein-1 participates in the regulation of fatty acid synthase expression in colorectal neoplasia. Exp. Cell Res. 261 (2000) 159-165
70. Yang Y.A., Han W.F., Morin P.J., Chrest F.J., and Pizer E.S. Activation of fatty acid synthesis during neoplastic transformation: role of mitogen-activated protein kinase and phosphatidylinositol 3-kinase. Exp. Cell Res. 279 (2002) 80-90
71. Yang Y.A., Morin P.J., Han W.F., Chen T., Bornman D.M., Gabrielson E.W., and Pizer E.S. Regulation of fatty acid synthase expression in breast cancer by sterol regulatory element binding protein-1c. Exp. Cell Res. 282 (2003) 132-137
72. Xiang X., Saha A.K., Wen R., Ruderman N.B., and Luo Z. AMP-activated protein kinase activators can inhibit the growth of prostate cancer cells by multiple mechanisms. Biochem. Biophys. Res. Commun. 321 (2004) 161-167
73. Swinnen J.V., Beckers A., Brusselmans K., Organe S., Segers J., Timmermans L., Vanderhoydonc F., Deboel L., Derua R., Waelkens E., De Schrijver E., Van de Sande T., Noël A., Foufelle F., and Verhoeven G. Mimicry of a cellular low energy status blocks tumor cell anabolism and suppresses the malignant phenotype. Cancer Res. 65 (2005) 2441-2448
74. Brunet J., Vazquez-Martin A., Colomer R., Graña-Suarez B., Martin-Castillo B., and Menendez J.A. BRCA1 and acetyl-CoA carboxylase: the metabolic syndrome of breast cancer. Mol. Carcinog. 47 (2008) 157-163
75. An Z., Wang H., Song P., Zhang M., Geng X., and Zou M.H. Nicotine-induced activation of AMP-activated protein kinase inhibits fatty acid synthase in 3T3L1 adipocytes: a role for oxidant stress. J. Biol. Chem. 282 (2007) 26793-26801
76. Medghalchi S.M., Vadlamudi A., and Kuhajda F.P. Fatty acid synthase phosphorylation as a cancer biomarker. Proceedings of the 100th Annual Meeting of the American Association for Cancer Research; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR (2009) Abstract # 1580
77. Swinnen J.V., Van Veldhoven P.P., Timmermans L., De Schrijver E., Brusselmans K., Vanderhoydonc F., Van de Sande T., Heemers H., Heyns W., and Verhoeven G. Fatty acid synthase drives the synthesis of phospholipids partitioning into detergent-resistant membrane microdomains. Biochem. Biophys. Res. Commun. 302 (2003) 898-903
78. Helms J.B., and Zurzolo C. Lipids as targeting signals: lipid rafts and intracellular trafficking. Traffic 5 (2004) 247-254
79. Patra S.K. Dissecting lipid raft facilitated cell signaling pathways in cancer. Biochim. Biophys. Acta 1785 (2008) 182-206
80. Nagy P., Vereb G., Sebestyén Z., Horváth G., Lockett S.J., Damjanovich S., Park J.W., Jovin T.M., and Szöllosi J. Lipid rafts and the local density of ErbB proteins influence the biological role of homo- and heteroassociations of ErbB2. J. Cell Sci. 115 (2002) 4251-4262
81. Mocanu M.M., Fazekas Z., Petrás M., Nagy P., Sebestyén Z., Isola J., Tímár J., Park J.W., Vereb G., and Szöllosi J. Associations of ErbB2, beta1-integrin and lipid rafts on Herceptin (Trastuzumab) resistant and sensitive tumor cell lines. Cancer Lett. 227 (2005) 201-212
82. Sottocornola E., Misasi R., Mattei V., Ciarlo L., Gradini R., Garofalo T., Berra B., Colombo I., and Sorice M. Role of gangliosides in the association of ErbB2 with lipid rafts in mammary epithelial HC11 cells. FEBS J. 273 (2006) 1821-1830
83. Di Vizio D., Adam R.M., Kim J., Kim R., Sotgia F., Williams T., Demichelis F., Solomon K.R., Loda M., Rubin M.A., Lisanti M.P., and Freeman M.R. Caveolin-1 interacts with a lipid raft-associated population of fatty acid synthase. Cell Cycle 7 (2008) 2257-2267
84. Xing X., Wang S.C., Xia W., Zou Y., Shao R., Kwong K.Y., Yu Z., Zhang S., Miller S., Huang L., and Hung M.C. The ets protein PEA3 suppresses HER-2/neu overexpression and inhibits tumorigenesis. Nat. Med. 6 (2000) 189-195
85. Hung M.C., and Wang S.C. Suppressing HER2/neu-mediated cell transformation by transcriptional repressors. Breast Dis. 11 (2000) 133-144
86. Yu Z., Xia W., Wang H.Y., Wang S.C., Pan Y., Kwong K.Y., Hortobagyi G.N., and Hung M.C. Antitumor activity of an Ets protein, PEA3, in breast cancer cell lines MDA-MB-361DYT2 and BT474M1. Mol. Carcinog. 45 (2006) 667-675
87. Bauer D.E., Hatzivassiliou G., Zhao F., Andreadis C., and Thompson C.B. ATP citrate lyase is an important component of cell growth and transformation. Oncogene 24 (2005) 6314-6322
88. Hatzivassiliou G., Zhao F., Bauer D.E., Andreadis C., Shaw A.N., Dhanak D., Hingorani S.R., Tuveson D.A., and Thompson C.B. ATP citrate lyase inhibition can suppress tumor cell growth. Cancer Cell 8 (2005) 311-321
89. Swinnen J.V., Brusselmans K., and Verhoeven G. Increased lipogenesis in cancer cells: new players, novel targets. Curr. Opin. Clin. Nutr. Metab. Care 9 (2006) 358-365
90. Mashima T., Seimiya H., and Tsuruo T. De novo fatty-acid synthesis and related pathways as molecular targets for cancer therapy. Br. J. Cancer 100 (2009) 1369-1372
91. Wellen K.E., Hatzivassiliou G., Sachdeva U.M., Bui T.V., Cross J.R., and Thompson C.B. ATP-citrate lyase links cellular metabolism to histone acetylation. Science 324 (2009) 1076-1080
92. Milgraum L.Z., Witters L.A., Pasternack G.R., and Kuhajda F.P. Enzymes of the fatty acid synthesis pathway are highly expressed in in situ breast carcinoma. Clin. Cancer Res. 3 (1997) 2115-2120
93. Moncur J.T., Park J.P., Memoli V.A., Mohandas T.K., and Kinlaw W.B. The "Spot 14" gene resides on the telomeric end of the 11q13 amplicon and is expressed in lipogenic breast cancers: implications for control of tumor metabolism. Proc. Natl. Acad. Sci. U. S. A. 95 (1998) 6989-6994
94. Brusselmans K., De Schrijver E., Verhoeven G., and Swinnen J.V. RNA interference-mediated silencing of the acetyl-CoA-carboxylase-alpha gene induces growth inhibition and apoptosis of prostate cancer cells. Cancer Res. 65 (2005) 6719-6725
95. Chajès V., Cambot M., Moreau K., Lenoir G.M., and Joulin V. Acetyl-CoA carboxylase alpha is essential to breast cancer cell survival. Cancer Res. 66 (2006) 5287-5294
96. Beckers A., Organe S., Timmermans L., Scheys K., Peeters A., Brusselmans K., Verhoeven G., and Swinnen J.V. Chemical inhibition of acetyl-CoA carboxylase induces growth arrest and cytotoxicity selectively in cancer cells. Cancer Res. 67 (2007) 8180-8187
97. Wang C., Xu C., Sun M., Luo D., Liao D.F., and Cao D. Acetyl-CoA carboxylase-alpha inhibitor TOFA induces human cancer cell apoptosis. Biochem. Biophys. Res. Commun. 385 (2009) 302-306
98. Pitel F., Fillon V., Heimel C., Le Fur N., el Khadir-Mounier C., Douaire M., Gellin J., and Vignal A. Mapping of FASN and ACACA on two chicken microchromosomes disrupts the human 17q syntenic group well conserved in mammals. Mamm. Genome 9 (1998) 297-300
99. Menendez J.A., Lupu R., and Colomer R. Obesity, fatty acid synthase, and cancer: serendipity or forgotten causal linkage?. Mol. Genet. Metab. 84 (2005) 293-295
100. Menendez J.A., Vellon L., and Lupu R. DNA topoisomerase IIalpha (TOP2A) inhibitors up-regulate fatty acid synthase gene expression in SK-Br3 breast cancer cells: in vitro evidence for a 'functional amplicon' involving FAS, Her-2/neu and TOP2A genes. Int. J. Mol. Med. 18 (2006) 1081-1087
101. Tripathy D., and Benz C.C. Activated oncogenes and putative tumor suppressor genes involved in human breast cancers. Cancer Treat. Res. 63 (1992) 15-60
102. Shah U.S., Dhir R., Gollin S.M., Chandran U.R., Lewis D., Acquafondata M., and Pflug B.R. Fatty acid synthase gene overexpression and copy number gain in prostate adenocarcinoma. Hum. Pathol. 37 (2006) 401-409
103. Oskouian B. Overexpression of fatty acid synthase in SKBR3 breast cancer cell line is mediated via a transcriptional mechanism. Cancer Lett. 149 (2000) 43-51
104. Kourtidis A., Carkner R., Brosnan J., and Conklin D. An RNAi screen identifies enhanced triglyceride storage as a survival factor for breast cancer cells with the ERBB2 amplicon. Proceedings of the 99th Annual Meeting of the American Association for Cancer Research; 2008 Apr 12-16; San Diego (CA): AACR (2008) Abstract # 938
105. Kourtidis A., Srinivasaiah R., Carkner R.D., Brosnan M.J., and Conklin D.S. Peroxisome proliferator-activated receptor-gamma protects ERBB2-positive breast cancer cells from palmitate toxicity. Breast Cancer Res. 11 (2009) R16
106. Zhu Y., Kan L., Qi C., Kanwar Y.S., Yeldandi A.V., Rao M.S., and Reddy J.K. Isolation and characterization of peroxisome proliferator-activated receptor (PPAR) interacting protein (PRIP) as a coactivator for PPAR. J. Biol. Chem. 275 (2000) 13510-13516
107. Misra P., Owuor E.D., Li W., Yu S., Qi C., Meyer K., Zhu Y.J., Rao M.S., Kong A.N., and Reddy J.K. Phosphorylation of transcriptional coactivator peroxisome proliferator-activated receptor (PPAR)-binding protein (PBP). Stimulation of transcriptional regulation by mitogen-activated protein kinase. J. Biol. Chem. 277 (2002) 48745-48754
108. Jia Y., Qi C., Kashireddi P., Surapureddi S., Zhu Y.J., Rao M.S., Le Roith D., Chambon P., Gonzalez F.J., and Reddy J.K. Transcription coactivator PBP, the peroxisome proliferator-activated receptor (PPAR)-binding protein, is required for PPARalpha-regulated gene expression in liver. J. Biol. Chem. 279 (2004) 24427-24434
109. Fontaine C., Dubois G., Duguay Y., Helledie T., Vu-Dac N., Gervois P., Soncin F., Mandrup S., Fruchart J.C., Fruchart-Najib J., and Staels B. The orphan nuclear receptor Rev-Erbalpha is a peroxisome proliferator-activated receptor (PPAR) gamma target gene and promotes PPARgamma-induced adipocyte differentiation. J. Biol. Chem. 278 (2003) 37672-37680
110. Laitinen S., Fontaine C., Fruchart J.C., and Staels B. The role of the orphan nuclear receptor Rev-Erb alpha in adipocyte differentiation and function. Biochimie 87 (2005) 21-25
111. Wang J., and Lazar M.A. Bifunctional role of Rev-erbalpha in adipocyte differentiation. Mol. Cell. Biol. 28 (2008) 2213-2220
112. Merida I., and Avila-Flores A. Tumor metabolism: new opportunities for cancer therapy. Clin. Transl. Oncol. 8 (2006) 711-716
113. Deberardinis R.J., Sayed N., Ditsworth D., and Thompson C.B. Brick by brick: metabolism and tumor cell growth. Curr. Opin. Genet. Dev. 18 (2008) 54-61
114. Jones R.G., and Thompson C.B. Tumor suppressors and cell metabolism: a recipe for cancer growth. Genes Dev. 23 (2009) 537-548
115. Thompson C.B. Metabolic enzymes as oncogenes or tumor suppressors. N. Engl. J. Med. 360 (2009) 813-815
116. Vander Heiden M.G., Cantley L.C., and Thompson C.B. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324 (2009) 1029-1033
117. Walczak R., and Tontonoz P. PPARadigms and PPARadoxes: expanding roles for PPARgamma in the control of lipid metabolism. J. Lipid Res. 43 (2002) 177-186
118. Gray S.L., Dalla Nora E., and Vidal-Puig A.J. Mouse models of PPAR-gamma deficiency: dissecting PPAR-gamma's role in metabolic homoeostasis. Biochem. Soc. Trans. 33 (2005) 1053-1058
119. Lehrke M., and Lazar M.A. The many faces of PPARgamma. Cell 123 (2005) 993-999
120. Medina-Gomez G., Gray S., and Vidal-Puig A. Adipogenesis and lipotoxicity: role of peroxisome proliferator-activated receptor gamma (PPARgamma) and PPARgammacoactivator-1 (PGC1). Public Health Nutr. 10 (2007) 1132-1137
121. Gray S.L., and Vidal-Puig A.J. Adipose tissue expandability in the maintenance of metabolic homeostasis. Nutr. Rev. 65 (2007) S7-S12
122. Yang Z., Bagheri-Yarmand R., Balasenthil S., Hortobagyi G., Sahin A.A., Barnes C.J., and Kumar R. HER2 regulation of peroxisome proliferator-activated receptor gamma (PPARgamma) expression and sensitivity of breast cancer cells to PPARgamma ligand therapy. Clin. Cancer Res. 9 (2003) 3198-3203
123. Nahta R., and Esteva F.J. Herceptin: mechanisms of action and resistance. Cancer Lett. 232 (2006) 123-138
124. Nahta R., and Esteva F.J. HER2 therapy: molecular mechanisms of trastuzumab resistance. Breast Cancer Res. 8 (2006) 215
125. Nahta R., and Esteva F.J. Trastuzumab: triumphs and tribulations. Oncogene 26 (2007) 3637-3643
126. Loftus T.M., Jaworsky D.E., Frehywot G.L., Townsend C.A., Ronnett G.V., Lane M.D., and Kuhajda F.P. Reduced food intake and body weight in mice treated with fatty acid synthase inhibitors. Science 288 (2000) 2379-2381
127. Takahashi K.A., Smart J.L., Liu H., and Cone R.D. The anorexigenic fatty acid synthase inhibitor, C75, is a nonspecific neuronal activator. Endocrinology 145 (2004) 184-193
128. Tu Y., Thupari J.N., Kim E.K., Pinn M.L., Moran T.H., Ronnett G.V., and Kuhajda F.P. C75 alters central and peripheral gene expression to reduce food intake and increase energy expenditure. Endocrinology 146 (2005) 486-493
129. Kuhajda F.P., Landree L.E., and Ronnett G.V. The connections between C75 and obesity drug-target pathways. Trends Pharmacol. Sci. 26 (2005) 541-544
130. Michalik L., Desvergne B., and Wahli W. Peroxisome-proliferator-activated receptors and cancers: complex stories. Nat. Rev., Cancer 4 (2004) 61-70
131. Grommes C., Landreth G.E., and Heneka M.T. Antineoplastic effects of peroxisome proliferator-activated receptor gamma agonists. Lancet Oncol. 5 (2004) 419-429
132. Ondrey F. Peroxisome proliferator-activated receptor gamma pathway targeting in carcinogenesis: implications for chemoprevention. Clin. Cancer Res. 15 (2009) 2-8
133. Fenner M.H., and Elstner E. Peroxisome proliferator-activated receptor-gamma ligands for the treatment of breast cancer. Expert Opin. Investig. Drugs 14 (2005) 557-568
134. Saez E., Rosenfeld J., Livolsi A., Olson P., Lombardo E., Nelson M., Banayo E., Cardiff R.D., Izpisua-Belmonte J.C., and Evans R.M. PPAR gamma signaling exacerbates mammary gland tumor development. Genes Dev. 18 (2004) 528-540
135. Mueller E., Sarraf P., Tontonoz P., Evans R.M., Martin K.J., Zhang M., Fletcher C., Singer S., and Spiegelman B.M. Terminal differentiation of human breast cancer through PPAR gamma. Mol. Cell 1 (1998) 465-470
136. Menendez J.A., Locker G., and Lupu R. Regulation of Fatty Acid Synthase (FAS) gene expression by Peroxisome Proliferator-activated receptor-gamma (PPARγ) is dependent of Her-2/neu (erbB-2) signaling in breast cancer cells. AACR Meeting Abstracts 2005 Vol. 46 (2005) 877-b, Abstract #3722
137. Pignatelli M., Cortés-Canteli M., Lai C., Santos A., and Perez-Castillo A. The peroxisome proliferator-activated receptor gamma is an inhibitor of ErbBs activity in human breast cancer cells. J. Cell Sci. 114 (2001) 4117-4126
138. Menendez J.A., Mehmi I., and Lupu R. Trastuzumab in combination with heregulin-activated Her-2 (erbB-2) triggers a receptor-enhanced chemosensitivity effect in the absence of Her-2 overexpression. J. Clin. Oncol. 24 (2006) 3735-3746
139. Menendez J.A., Ropero S., Lupu R., and Colomer R. Dietary fatty acids regulate the activation status of Her-2/neu (c-erbB-2) oncogene in breast cancer cells. Ann. Oncol. 15 (2004) 1719-1721
140. Menendez J.A., Vellon L., Colomer R., and Lupu R. Oleic acid, the main monounsaturated fatty acid of olive oil, suppresses Her-2/neu (erbB-2) expression and synergistically enhances the growth inhibitory effects of trastuzumab (Herceptin) in breast cancer cells with Her-2/neu oncogene amplification. Ann. Oncol. 2005 (2005) 359-371
141. Menendez J.A., and Lupu R. Mediterranean dietary traditions for the molecular treatment of human cancer: anti-oncogenic actions of the main olive oil's monounsaturated fatty acid oleic acid (18:1n-9). Curr. Pharm. Biotechnol. 7 (2006) 495-502
142. Menendez J.A., Papadimitropoulou A., Vellon L., and Lupu R. A genomic explanation connecting "Mediterranean diet", olive oil and cancer: oleic acid, the main monounsaturated fatty acid of olive oil, induces formation of inhibitory "PEA3 transcription factor-PEA3 DNA binding site" complexes at the Her-2/neu (erbB-2) oncogene promoter in breast, ovarian and stomach cancer cells. Eur. J. Cancer 42 (2006) 2425-2432
143. Colomer R., and Menéndez J.A. Mediterranean diet, olive oil and cancer. Clin. Transl. Oncol. 8 (2006) 15-21
144. Colomer R., Lupu R., Papadimitropoulou A., Vellón L., Vázquez-Martín A., Brunet J., Fernández-Gutiérrez A., Segura-Carretero A., and Menéndez J.A. Giacomo Castelvetro's salads. Anti-HER2 oncogene nutraceuticals since the 17th century. Clin. Transl. Oncol. 10 (2008) 30-34
145. Sant M., Allemani C., Sieri S., Krogh V., Menard S., Tagliabue E., Nardini E., Micheli A., Crosignani P., Muti P., and Berrino F. Salad vegetables dietary pattern protects against HER-2-positive breast cancer: a prospective Italian study. Int. J. Cancer 121 (2007) 911-914
146. Menendez J.A., Lupu R., and Colomer R. Exogenous supplementation with omega-3 polyunsaturated fatty acid docosahexaenoic acid (DHA; 22:6n-3) synergistically enhances taxane cytotoxicity and downregulates Her-2/neu (c-erbB-2) oncogene expression in human breast cancer cells. Eur. J. Cancer Prev. 14 (2005) 263-270
147. Menéndez J.A., Vázquez-Martín A., Ropero S., Colomer R., and Lupu R. HER2 (erbB-2)-targeted effects of the omega-3 polyunsaturated fatty acid, alpha-linolenic acid (ALA; 18:3n-3), in breast cancer cells: the "fat features" of the "Mediterranean diet" as an "anti-HER2 cocktail". Clin. Transl. Oncol. 8 (2006) 812-820
148. Menendez J.A., Vellon L., Colomer R., and Lupu R. Effect of gamma-linolenic acid on the transcriptional activity of the Her-2/neu (erbB-2) oncogene. J. Natl. Cancer Inst. 97 (2005) 1611-1615
149. Harrington M., Pond-Tor S., and Boney C.M. Role of epidermal growth factor and ErbB2 receptors in 3T3-L1 adipogenesis. Obesity (Silver Spring) 15 (2007) 563-571
150. Vazquez-Martin A., Ortega-Delgado F.J., Fernandez-Real J.M., and Menendez J.A. The tyrosine kinase receptor HER2 (erbB-2): from oncogenesis to adipogenesis. J. Cell. Biochem. 105 (2008) 1147-1152
151. Gatenby R.A., and Gillies R.J. A microenvironmental model of carcinogenesis. Nat. Rev., Cancer 8 (2008) 56-60