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Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis

Key Points

  • A wide variety of tumours and their precursor lesions undergo exacerbated de novo biogenesis of fatty acids (FAs) irrespective of the levels of circulating lipids. Neoplastic lipogenesis is reflected by significantly increased activity and coordinate expression of several lipogenic enzymes in tumour cells. Upregulation of fatty acid synthase (FASN), the key metabolic multi-enzyme that is responsible for the terminal catalytic step in FA synthesis, represents a nearly-universal phenotypic alteration in most human malignancies.

  • Although the same disturbances in signalling pathways responsible for oncogenic transformation can contribute to increased lipogenesis in tumours, FASN hyperactivity and overexpression is not only a secondary phenomenon that results from the induction of other pathways during carcinogenesis. Rather, it is directly selected for because it provides a growth and/or survival advantage achieved through multiple mechanisms.

  • Early upregulation of FASN in precursor lesions might represent an obligatory metabolic acquisition in response to the microenvironment of pre-invasive lesions (that is, poor oxygenation and high acidity, and/or lack of nutrients), which continue to occur in invasive and/or metastatic stages. The functional and temporal linkage of the 'glycolytic-switch' and the FASN-related lipogenic phenotype may represent co-evolved essential components of the malignant phenotype and, therefore, hallmarks of invasive cancers.

  • Both the persistent prevalence of the exacerbated de novo FA biosynthesis in primary and metastatic malignancy and the existence of bi-directional linkages of FASN with cancer-controlling networks (such as oestrogen receptor and ERBB2), strongly suggest that FASN can work as a previously unrecognized metabolic intermediate of oncogenesis linking energy, anabolism and malignant transformation.

  • As exacerbated lipogenesis emerges early in carcinogenesis, it might represent an exploitable target in cancer prevention by retarding the progression of pre-malignant lesions. At later stages, a more complete understanding of the molecular and physiological consequences of its specific inhibition might lead to targeted therapies for the treatment of advanced or metastatic carcinomas.

Abstract

There is a renewed interest in the ultimate role of fatty acid synthase (FASN) — a key lipogenic enzyme catalysing the terminal steps in the de novo biogenesis of fatty acids — in cancer pathogenesis. Tumour-associated FASN, by conferring growth and survival advantages rather than functioning as an anabolic energy-storage pathway, appears to necessarily accompany the natural history of most human cancers. A recent identification of cross-talk between FASN and well-established cancer-controlling networks begins to delineate the oncogenic nature of FASN-driven lipogenesis. FASN, a nearly-universal druggable target in many human carcinomas and their precursor lesions, offers new therapeutic opportunities for metabolically treating and preventing cancer.

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Figure 1: Connecting glucose metabolism and fatty acid biosynthesis pathways in tumour cells.
Figure 2: Two main pathways to regulate the expression of tumour-associated FASN.
Figure 3: Modulation of SREBP1c: a common partner for FASN regulation in normal and tumour cells.
Figure 4: The 'lipogenic phenotype' and cell–environment interactions in carcinogenesis: a working model.

References

  1. 1

    Warburg, O. On the origin of cancer cells. Science 123, 309–314 (1956).

    CAS  Article  Google Scholar 

  2. 2

    Garber, K. Energy boost: the Warburg effect returns in a new theory of cancer. J. Natl Cancer Inst. 96, 1805–1806 (2004).

    PubMed  Article  Google Scholar 

  3. 3

    Shaw, R. J. Glucose metabolism and cancer. Curr. Opin. Cell Biol. 18, 598–608 (2006).

    CAS  Article  PubMed  Google Scholar 

  4. 4

    Bui, T. & Thompson, C. B. Cancer's sweet tooth. Cancer Cell 9, 419–420 (2006).

    CAS  PubMed  Article  Google Scholar 

  5. 5

    Garber, K. Energy deregulation: licensing tumors to grow. Science 312, 1158–1159 (2006).

    CAS  PubMed  Article  Google Scholar 

  6. 6

    Clemens, M. J. Targets and mechanisms for the regulation of translation in malignant transformation. Oncogene 23, 3180–3188 (2004).

    CAS  Article  PubMed  Google Scholar 

  7. 7

    Averous, J. & Proud, C. G. When translation meets transformation: the mTOR story. Oncogene 25, 6423–6435 (2006).

    CAS  PubMed  Article  Google Scholar 

  8. 8

    Voeller, D., Rahman, L. & Zajac-Kaye, M. Elevated levels of thymidylate synthase linked to neoplastic transformation of mammalian cells. Cell Cycle 3, 1005–1007 (2004).

    CAS  PubMed  Article  Google Scholar 

  9. 9

    Rahman, L. et al. Thymidylate synthase as an oncogene: a novel role for an essential DNA synthesis enzyme. Cancer Cell 5, 341–351 (2004).

    CAS  PubMed  Article  Google Scholar 

  10. 10

    Kuhajda, F. P. Fatty-acid Synthase and human cancer: new perspectives on its role in tumor biology. Nutrition 16, 202–208 (2000). First review documenting the relationship between FASN-catalysed endogenous FA biogenesis and tumour biology.

    CAS  PubMed  Article  Google Scholar 

  11. 11

    Wakil, S. J. Structure and function of animal fatty acid synthase. Lipids 39, 1045–1053 (2004).

    PubMed  Article  Google Scholar 

  12. 12

    Asturias, F. J. et al. Structure and molecular organization of mammalian fatty acid synthase. Nature Struct. Mol. Biol. 12, 225–232 (2005).

    CAS  Article  Google Scholar 

  13. 13

    Maier, T., Jenni, S. & Ban, N. Architecture of mammalian fatty acid synthase at 4.5 Å resolution. Science 311, 1258–1262 (2006). Revealed the architecture of mammalian FASN at 4.5 Å resolution for the first time.

    CAS  PubMed  Article  Google Scholar 

  14. 14

    Weiss, L. et al. Fatty-acid biosynthesis in man, a pathway of minor importance. Purification, optimal assay conditions, and organ distribution of fatty-acid synthase. Biol. Chem. Hoppe Seyler 367, 905–912 (1986).

    CAS  PubMed  Article  Google Scholar 

  15. 15

    Wagle, S. et al. Hormonal regulation and cellular localization of fatty acid synthase in human fetal lung. Am. J. Physiol. 277, 381–390 (1999).

    Google Scholar 

  16. 16

    Kusakabe, T. et al. Fatty acid synthase is expressed mainly in adult hormone-sensitive cells or cells with high lipid metabolism and in proliferating fetal cells. J. Histochem. Cytochem. 48, 613–622 (2000).

    CAS  PubMed  Article  Google Scholar 

  17. 17

    Pizer, E. S. et al. Expression of fatty acid synthase is closely linked to proliferation and stromal decidualization in cycling endometrium. Int. J. Gynecol. Pathol. 16, 45–51 (1997).

    CAS  PubMed  Article  Google Scholar 

  18. 18

    Anderson, S. M. et al. Key stages in mammary gland development. Secretory activation in the mammary gland: it's not just about milk protein synthesis! Breast Cancer Res. 9, 204 (2007). An up-to-date review exhaustively describing all the hormonal regulation pathways that are involved in the mammary gland transition from pregnancy to lactating breast, a highly efficient lipid synthetic organ.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  19. 19

    Medes, G., Thomas, A. & Weinhouse, S. Metabolism of neoplastic tissue IV: a study of lipid synthesis in neoplastic tissue slices in vitro. Cancer Res. 13, 27–29 (1953). One of the pioneer studies describing the existence of exacerbated endogenous FA metabolism in tumour tissues.

    CAS  PubMed  Google Scholar 

  20. 20

    Szutowicz, A., Kwiatkowski, J. & Angielski, S. Lipogenetic and glycolytic enzyme activities in carcinoma and nonmalignant diseases of the human breast. Br. J. Cancer 39, 681–687 (1979).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. 21

    Kuhajda, F. P., Piantadosi, S. & Pasternack, G. P. Haptoglobin-related protein (Hpr) epitopes in breast cancer as a predictor of recurrence of the disease. N. Engl. J. Med. 321, 636–641 (1989).

    CAS  PubMed  Article  Google Scholar 

  22. 22

    Kuhajda, F. P. et al. Fatty acid synthesis: a potential selective target for antineoplastic therapy. Proc. Natl Acad. Sci. USA 91, 6379–6383 (1994). Key finding characterizing the breast tumour-associated protein OA-519 as the enzyme FASN.

    CAS  PubMed  Article  Google Scholar 

  23. 23

    Menendez, J. A. & 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, 414–426 (2004).

    CAS  Google Scholar 

  24. 24

    Swinnen, J. V., Brusselmans, K. & Verhoeven, G. Increased lipogenesis in cancer cells: new players, novel targets. Curr. Opin. Clin. Nutr. Metab. Care 9, 358–365 (2006).

    CAS  PubMed  Article  Google Scholar 

  25. 25

    Menendez, J. A. & 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, 346–357 (2006).

    CAS  PubMed  Article  Google Scholar 

  26. 26

    Kuhajda, F. P. Fatty acid synthase and cancer: new application of an old pathway. Cancer Res. 66, 5977–5980 (2006).

    CAS  PubMed  Article  Google Scholar 

  27. 27

    Jackowski, S. Coordination of membrane phospholipid synthesis with cell cycle. J. Biol. Chem. 269, 3858–3867 (1994).

    CAS  PubMed  Google Scholar 

  28. 28

    Costello, L. C. & Franklin, R. B. Tumor cell metabolism: the marriage of molecular genetics and proteomics with cellular intermediary metabolism; proceed with caution. Molecular Cancer 5, 59 (2006).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  29. 29

    Costello, L. C. & Franklin, R. B. “Why do tumour cells glycolyse”?: from glycolysis through citrate to lipogenesis. Mol. Cell. Biochem. 280, 1–8 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. 30

    Pizer, E. S. et al. Fatty acid synthase (FAS): A target for cytotoxic metabolites in HL60 promyelocitic leukemia cells. Cancer Res. 56, 745–751 (1996).

    CAS  PubMed  Google Scholar 

  31. 31

    Swinnen, J. V. et al. Fatty acid synthase drives the synthesis of phospholipids partitioning into detergent-resistant membrane microdomains. Biochem. Biophys. Res. Commun. 302, 898–903 (2003).

    CAS  PubMed  Article  Google Scholar 

  32. 32

    Bauer, D. E. et al. ATP citrate lyase is an important component of cell growth and transformation. Oncogene 24, 6314–6322 (2005).

    CAS  PubMed  Article  Google Scholar 

  33. 33

    Hatzivassiliou, G. et al. ATP citrate lyase inhibition can suppress tumor cell growth. Cancer Cell 8, 311–321 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. 34

    Tong, L. Acetyl-coenzyme A carboxylase: crucial metabolic enzyme and attractive target for drug discovery. Cell. Mol. Life Sci. 62, 1784–1803 (2005).

    CAS  PubMed  Article  Google Scholar 

  35. 35

    Milgraum, L. Z. et al. Enzymes of the fatty acid synthase pathway are highly expressed in in situ breast carcinoma. Clin. Cancer Res. 3, 2115–2120 (1997).

    CAS  PubMed  Google Scholar 

  36. 36

    Brusselmans, K. et al. RNA interference-mediated silencing of the acetyl-CoA carboxylase-α gene induces growth inhibition and apoptosis of prostate cancer cells. Cancer Res. 65, 6719–6725 (2005).

    CAS  PubMed  Article  Google Scholar 

  37. 37

    Chajès, V. et al. Acetyl-CoA carboxylase α is essential to breast cancer cell survival. Cancer Res. 66, 5287–5294 (2006).

    PubMed  Article  CAS  Google Scholar 

  38. 38

    Sinilnikova, O. M. et al. Acetyl-CoA carboxylase α gene and breast cancer susceptibility. Carcinogenesis 25, 2417–2424 (2004).

    CAS  PubMed  Article  Google Scholar 

  39. 39

    Sinilnikova, O. M. et al. Haplotype-based analysis of common variation in the acetyl-CoA carboxylase a gene and breast cancer risk: A case-control study nested within the European Prospective Investigation into Cancer and Nutrition. Cancer Epidemiol. Biomarkers Prev. 16, 409–415 (2007).

    CAS  PubMed  Article  Google Scholar 

  40. 40

    Chin, K. et al. Genomic and transcriptional aberrations linked to breast cancer pathophysiologies. Cancer Cell 10, 529–541 (2006).

    CAS  Article  PubMed  Google Scholar 

  41. 41

    Jensen, V. et al. The prognostic value of oncogenic antigen-519 (OA-519) expression and proliferative activity detected by antibody MIB-1 in node-negative breast cancer. J. Pathol. 176, 343–352 (1995).

    CAS  PubMed  Article  Google Scholar 

  42. 42

    Alo, P. L. et al. Expression of fatty acid synthase (FAS) as a predictor of recurrence in stage I breast carcinoma patients. Cancer 77, 474–482 (1996).

    CAS  PubMed  Article  Google Scholar 

  43. 43

    Gansler, T. S. et al. Increased expression of fatty acid synthase (OA-519) in ovarian neoplasms predicts shorter survival. Hum. Pathol. 28, 686–692 (1997).

    CAS  PubMed  Article  Google Scholar 

  44. 44

    Alo, P. L. et al. Fatty acid synthase (FAS) predictive strength in poorly differentiated early breast carcinomas. Tumori. 85, 35–40 (1999).

    CAS  PubMed  Article  Google Scholar 

  45. 45

    Visca, P. et al. Fatty acid synthase (FAS) is a marker of increased risk of recurrence in lung carcinoma. Anticancer Res. 24, 4169–4173 (2004).

    CAS  PubMed  Google Scholar 

  46. 46

    Sebastian, V. et al. Fatty acid synthase is a marker of increased risk of recurrence in endometrial carcinoma. Gynecol. Oncol. 92, 101–105 (2004).

    Article  CAS  Google Scholar 

  47. 47

    Bandyopadhyay, S. et al. FAS expression inversely correlates with PTEN level in prostate cancer and a PI 3-kinase inhibitor synergizes with FAS siRNA to induce apoptosis. Oncogene 24, 5389–5395 (2005).

    CAS  PubMed  Article  Google Scholar 

  48. 48

    Sinclair, C. S. et al. The 17q23 amplicon and breast cancer. Breast Cancer Res. Treat. 78, 313–322 (2003).

    CAS  PubMed  Article  Google Scholar 

  49. 49

    Shah, U. S. et al. Fatty acid synthase gene overexpression and copy number gain in prostate adenocarcinoma. Hum. Pathol. 37, 401–409 (2006).

    CAS  PubMed  Article  Google Scholar 

  50. 50

    Katsurada, A. et al. Effects of nutrients and hormones on transcriptional and post-transcriptional regulation of fatty acid synthase in liver. Eur. J. Biochem. 190, 427–433 (1990).

    CAS  PubMed  Article  Google Scholar 

  51. 51

    Sul, H. S. & Wang, D. Nutritional and hormonal regulation of enzymes in fat synthesis: studies of fatty acid synthase and mitochondrial glycerol-3-phosphate acyltransferase gene transcription. Annu. Rev. Nutr. 18, 331–351 (1998).

    CAS  PubMed  Article  Google Scholar 

  52. 52

    Fukuda, H. et al. Transcriptional regulation of fatty acid synthase by insulin/glucose, polyunsaturated fatty acids and leptin in hepatocytes and adipocytes in normal and genetically obese rats. Eur. J. Biochem. 260, 505–511 (1999).

    CAS  PubMed  Article  Google Scholar 

  53. 53

    Swinnen, J. V. et al. Stimulation of tumor-associated fatty acid synthase expression by growth factor activation of the sterol regulatory element-binding protein pathway. Oncogene 19, 5173–5181 (2000). First study to reveal how exacerbated GF–GFR signalling in cancer cells constitutively upregulates tumour-associated FASN.

    CAS  PubMed  Article  Google Scholar 

  54. 54

    Oskouian, B. Overexpression of fatty acid synthase in SKBR3 breast cancer cell line is mediated via a transcriptional mechanism. Cancer Lett. 149, 43–51 (2000).

    CAS  PubMed  Article  Google Scholar 

  55. 55

    Kumar-Sinha, C. et al. Transcriptome analysis of HER2 reveals a molecular connection to fatty acid synthesis. Cancer Res. 63, 132–139 (2003).

    CAS  PubMed  Google Scholar 

  56. 56

    Menendez, J. A. et al. 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, 1369–1383 (2004).

    CAS  PubMed  Google Scholar 

  57. 57

    Menendez, J. A. et al. 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, 164–178 (2004).

    CAS  PubMed  Article  Google Scholar 

  58. 58

    Zhang, D. et al. 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, 1686–1696 (2005).

    CAS  PubMed  Article  Google Scholar 

  59. 59

    Van de Sande, T. et al. Role of the phosphatidylinositol 3′-kinase/PTEN/Akt kinase pathway in the overexpression of fatty acid synthase in LNCaP prostate cancer cells. Cancer Res. 62, 642–646 (2002).

    CAS  PubMed  Google Scholar 

  60. 60

    Porstmannm, T. et al. PKB/AKT induces transcription of enzymes involved in cholesterol and fatty acid biosynthesis via activation of SREBP. Oncogene 24, 6465–6481 (2005).

    Article  CAS  Google Scholar 

  61. 61

    Yang, Y. A. et al. Activation of fatty acid synthesis during neoplastic transformation: role of mitogen-activated protein kinase and phosphatidylinositol 3-kinase. Exp. Cell Res. 279, 80–90 (2002).

    CAS  PubMed  Article  Google Scholar 

  62. 62

    Wang, H. Q. et al. Positive feedback regulation between AKT activation and fatty acid synthase expression in ovarian carcinoma cells. Oncogene 24, 3574–3582 (2005).

    CAS  PubMed  Article  Google Scholar 

  63. 63

    Chalbos, D. et al. Fatty acid synthetase and its mRNA are induced by progestins in breast cancer cells. J. Biol. Chem. 262, 9923–9926 (1987).

    CAS  PubMed  Google Scholar 

  64. 64

    Swinnen, J. V. et al. Androgens stimulate fatty acid synthase in the human prostate cancer cell line LNCaP. Cancer Res. 57, 1086–1090 (1997).

    CAS  PubMed  Google Scholar 

  65. 65

    Menendez, J. A. et al. The estrogenic activity of synthetic progestins used in oral contraceptives enhances fatty acid synthase-dependent breast cancer cell proliferation and survival. Int. J. Oncol. 26, 1507–1515 (2005).

    CAS  PubMed  Google Scholar 

  66. 66

    Lupu, R. & Menendez, J. A. Targeting fatty acid synthase in breast and endometrial cancer: An alternative to selective estrogen receptor modulators? Endocrinology 147, 4056–4066 (2006). This review provides new insights on the cross-talk between tumour-associated FASN and oestrogen receptor (ER) in hormone-sensitive human tumours.

    CAS  PubMed  Article  Google Scholar 

  67. 67

    Rawson, R. B. The SREBP pathway—insights from Insigs and insects. Nature Rev. Mol. Cell Biol. 4, 631–640 (2003).

    CAS  Article  Google Scholar 

  68. 68

    Eberle, D. et al. SREBP transcription factors: master regulators of lipid homeostasis. Biochimie. 86, 839–848 (2004). References 67 and 68 brilliantly review the role of SREBP transcription factors as master regulators of lipid homeostasis.

    CAS  PubMed  Article  Google Scholar 

  69. 69

    Kim, J. B. et al. Nutritional and insulin regulation of fatty acid synthetase and leptin gene expression through ADD1/SREBP1. J. Clin. Invest. 101, 1–9 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  70. 70

    Shimano, H. et al. Sterol regulatory element-binding protein 1 as a key transcription factor for nutritional induction of lipogenic enzymes genes. J. Biol. Chem. 274, 35832–35839 (1999).

    CAS  PubMed  Article  Google Scholar 

  71. 71

    Fleischmann, M. & Iynedjian, P. B. Regulation of sterol regulatory-element binding protein 1 gene expression in liver: role of insulin and protein kinase B/cAkt. Biochem. J. 349, 13–17 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  72. 72

    Kotzka, J. et al. Sterol regulatory element binding proteins (SREBP)-1a and SREBP-2 are linked to the MAP-kinase cascade. J. Lipid Res. 41, 99–108 (2000).

    CAS  PubMed  Google Scholar 

  73. 73

    Kersten, S. Mechanisms of nutritional and hormonal regulation of lipogenesis. EMBO Rep. 2, 282–286 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. 74

    Swinnen, J. V. et al. Coordinate regulation of lipogenic gene expression by androgens: evidence for a cascade mechanism involving sterol regulatory element binding proteins. Proc. Natl Acad. Sci. USA 94, 12975–12980 (1997).

    CAS  PubMed  Article  Google Scholar 

  75. 75

    Yang, Y. A. et al. Regulation of fatty acid synthase expression in breast cancer by sterol regulatory elements binding protein-1c. Exp. Cell Res. 282, 132–137 (2003).

    CAS  PubMed  Article  Google Scholar 

  76. 76

    Ettinger, S. L. et al. Dysregulation of sterol response element-binding proteins and downstream effectors in prostate cancer during progression to androgen independence. Cancer Res. 64, 2212–2221 (2004).

    CAS  PubMed  Article  Google Scholar 

  77. 77

    Menendez, J. A., Decker, J. P. & 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, 1–4 (2005).

    CAS  PubMed  Article  Google Scholar 

  78. 78

    Heemers, H. et al. Androgens stimulate lipogenic gene expression in prostate cancer cells by activation of the sterol regulatory element-binding protein cleavage activating protein/sterol regulatory element-binding protein pathway. Mol. Endocrinol. 15, 1817–1828 (2001).

    CAS  PubMed  Article  Google Scholar 

  79. 79

    Menendez, J. A., Colomer, R. & Lupu, R. Why does tumor-associated fatty acid synthase (oncogenic antigen-519) ignore dietary fatty acids? Med. Hypotheses 64, 342–349 (2005).

    CAS  PubMed  Article  Google Scholar 

  80. 80

    Li, J. N. et al. Sterol regulatory element-binding protein-1 participates in the regulation of fatty acid synthase expression in colorectal neoplasia. Exp. Cell. Res. 261, 159–165 (2000).

    CAS  PubMed  Article  Google Scholar 

  81. 81

    Swinnen, J. V. Increased lipogenesis in steroid-responsive cancer cells: mechanisms of regulation, role in cancer cell biology and perspectives on clinical applications. Verh. K. Acad. Geneeskd. Belg. 63, 321–333 (2001).

    CAS  PubMed  Google Scholar 

  82. 82

    Graner, E. et al. The isopeptidase USP2a regulates the stability of fatty acid synthase in prostate cancer. Cancer Cell 5, 253–261 (2004). The first study to describe how tumour-associated FASN overexpression can be achieved through protein stabilization.

    CAS  Article  Google Scholar 

  83. 83

    Priolo, C. et al. The isopeptidase USP2a protects human prostate cancer from apoptosis. Cancer Res. 66, 8625–8632 (2006).

    CAS  PubMed  Article  Google Scholar 

  84. 84

    Swinnen, J. V. et al. Selective activation of the fatty acid synthesis pathway in human prostate cancer. Int. J. Cancer 88, 176–179 (2000).

    CAS  PubMed  Article  Google Scholar 

  85. 85

    Swinnen, J. V. et al. Overexpression of fatty acid synthase is an early and common event in the development of prostate cancer. Int. J. Cancer 98, 19–22 (2002).

    CAS  PubMed  Article  Google Scholar 

  86. 86

    Esslimani-Sahla, M. et al. Increased expression of fatty acid synthase and progesterone receptor in early steps of human mammary carcinogenesis. Int. J. Cancer 120, 224–229 (2007).

    CAS  PubMed  Article  Google Scholar 

  87. 87

    Pizer, E. S. et al. Inhibition of fatty acid synthesis delays disease progression in a xenograft model of ovarian cancer. Cancer Res. 56, 1189–1193 (1996).

    CAS  PubMed  Google Scholar 

  88. 88

    Pizer, E. S. et al. Inhibition of fatty acid synthesis induces programmed cell death in human breast cancer cells. Cancer Res. 12, 2745–2747 (1996).

    Google Scholar 

  89. 89

    Pizer, E. S. et al. Pharmacological inhibitors of mammalian fatty acid synthase suppress DNA replication and induce apoptosis in tumor cell lines. Cancer Res. 58, 4611–4615 (1998).

    CAS  PubMed  Google Scholar 

  90. 90

    Pizer, E. S. et al. Malonyl-coenzyme-A is a potential mediator of cytotoxicity induced by fatty-acid synthase inhibition in human breast cancer cells and xenografts. Cancer Res. 60, 213–218 (2000).

    CAS  PubMed  Google Scholar 

  91. 91

    Li, J. N. et al. Pharmacological inhibition of fatty acid synthase activity produces both cytostatic and cytotoxic effects modulated by p53. Cancer Res. 61, 1493–1499 (2001).

    CAS  PubMed  Google Scholar 

  92. 92

    Kuhajda, F. P. et al. Synthesis and antitumor activity of an inhibitor of fatty acid synthase. Proc. Natl Acad. Sci. USA 97, 3450–3454 (2000).

    CAS  PubMed  Article  Google Scholar 

  93. 93

    Thupari, J. N., Pinn, M. L. & Kuhajda, F. P. Fatty acid synthase inhibition in human breast cancer cells leads to malonyl-CoA-induced inhibition of fatty acid oxidation and cytotoxicity. Biochem. Biophys. Res. Commun. 285, 217–223 (2001).

    CAS  PubMed  Article  Google Scholar 

  94. 94

    Heiligtag, S. J., Bredehorst, R. & Davidm K. A. Key role of mitochondria in cerulenin-mediated apoptosis. Cell Death Differ. 9, 1017–1025 (2002).

    CAS  PubMed  Article  Google Scholar 

  95. 95

    Liu, B. et al. Triclosan inhibits enoyl-reductase of type I fatty acid synthase in vitro and is cytotoxic to MCF-7 and SKBr-3 breast cancer cells. Cancer Chemother. Pharmacol. 49, 187–193 (2002).

    CAS  PubMed  Article  Google Scholar 

  96. 96

    Zhou, W. et al. Fatty acid synthase inhibition triggers apoptosis during S phase in human cancer cells. Cancer Res. 63, 7330–7337 (2003).

    CAS  PubMed  Google Scholar 

  97. 97

    Brusselmans, K. et al. Epigallocatechin-3-gallate is a potent natural inhibitor of fatty acid synthase in intact cells and selectively induces apoptosis in prostate cancer cells. Int. J. Cancer 106, 856–862 (2003).

    CAS  PubMed  Article  Google Scholar 

  98. 98

    Menendez, J. A. et al. 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, 4945–4958 (2004).

    CAS  PubMed  Article  Google Scholar 

  99. 99

    Menendez, J. A. et al. 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-κB. Int. J. Oncol. 24, 591–608 (2004).

    CAS  PubMed  Google Scholar 

  100. 100

    Kridel, S. J. et al. Orlistat is a novel inhibitor of fatty acid synthase with antitumor activity. Cancer Res. 64, 2070–2075 (2004).

    CAS  PubMed  Article  Google Scholar 

  101. 101

    Knowles, L. M. et al. A fatty acid synthase blockade induces tumor cell-cycle arrest by down-regulating Skp2. J. Biol. Chem. 279, 30540–30545 (2004).

    CAS  PubMed  Article  Google Scholar 

  102. 102

    Menendez, J. A., Vellon, L. & 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, 1253–1267 (2005).

    CAS  PubMed  Article  Google Scholar 

  103. 103

    Menendez, J. A. & 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, 33–40 (2005).

    CAS  PubMed  Google Scholar 

  104. 104

    Bandyopadhyay, S. et al. Mechanism of apoptosis induced by the inhibition of fatty acid synthase in breast cancer cells. Cancer Res. 66, 5934–5940 (2006).

    CAS  PubMed  Article  Google Scholar 

  105. 105

    Zhao, W. et al. Fatty acid synthase: a novel target for antiglioma therapy. Br. J. Cancer 95, 869–878 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  106. 106

    Lupu, R. & 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, 495–502 (2006).

    PubMed  Article  Google Scholar 

  107. 107

    Menendez, J. A. et al. Inhibition of fatty acid synthase (FAS) suppresses HER2/neu (erbB-2) oncogene overexpression in cancer cells. Proc. Natl Acad. Sci. USA 101, 10715–10720 (2004). First experimental evidence showing the ability of endogenous FA metabolism to specifically regulate well-characterized oncogenes such as ERBB2.

    CAS  PubMed  Article  Google Scholar 

  108. 108

    Menendez, J. A., Lupu, R. & Colomer, R. Targeting fatty acid synthase: potential for therapeutic intervention in Her-2/neu-overexpressing breast cancer. Drug News Perspect. 18, 375–385 (2005).

    CAS  PubMed  Article  Google Scholar 

  109. 109

    Gatenby, R. A. & Gawlinski, E. T. The glycolytic phenotype in carcinogenesis and tumor invasion: insights through mathematical models. Cancer Res. 63, 3847–3854 (2003).

    CAS  PubMed  Google Scholar 

  110. 110

    Gatenby, R. A. & Gillies, R. J. Why do cancers have high aerobic glycolysis? Nature Rev. Cancer 4, 891–899 (2004). A compelling opinion piece, in which the authors convincingly propose that the glycolytic phenotype confers a significant proliferative advantage during somatic evolution of cancer and must, therefore, be a crucial component of the malignant phenotype.

    CAS  Article  Google Scholar 

  111. 111

    Gillies, R. J. & Gatenby, R. A. Hypoxia and adaptive landscapes in the evolution of carcinogenesis. Cancer Metastasis Rev. 26, 311–317 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  112. 112

    Gatenby, R. A. & Gillies, R. J. Glycolysis in cancer: a potential target for therapy. Int. J. Biochem. Cell Biol. 39, 1358–1366 (2007).

    CAS  PubMed  Article  Google Scholar 

  113. 113

    Hochachka, P. W. Living without oxygen. 1–181 (Harvard University Press, Cambridge, USA, 1980).

    Book  Google Scholar 

  114. 114

    Hochachka, P. W. et al. Going malignant: the hypoxia-cancer connection in the prostate. Bioessays 24, 749–757 (2002).

    CAS  PubMed  Article  Google Scholar 

  115. 115

    Baron, A. et al. Fatty acid synthase: a metabolic oncogene in prostate cancer? J. Cell. Biochem. 91, 47–53 (2004).

    CAS  PubMed  Article  Google Scholar 

  116. 116

    Elstrom, R. L. et al. Akt stimulates aerobic glycolysis in cancer cells. Cancer Res. 64, 3892–3899 (2004).

    CAS  Article  Google Scholar 

  117. 117

    Buzzai, M. et al. The glucose dependence of Akt-transformed cells can be reversed by pharmacological activation of fatty acid-beta oxidation. Oncogene 24, 4165–4173 (2005).

    CAS  PubMed  Article  Google Scholar 

  118. 118

    Gatenby, R. A. et al. Acid-mediated tumor invasion: a multidisciplinary study. Cancer Res. 66, 5216–5223 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  119. 119

    Smallbone, K. et al. Metabolic changes during carcinogenesis: potential impact on invasiveness. J. Theor. Biol. 244, 703–713 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  120. 120

    Visca, P. et al. Immunohistochemical expression and prognostic significance of FAS and GLUT1 in bladder carcinoma. Anticancer Res. 23, 335–339 (2003).

    CAS  PubMed  Google Scholar 

  121. 121

    Alo, P. L. et al. Immunohistochemical expression of human erythrocyte glucose transporter and fatty acid synthase in infiltrating breast carcinomas and adjacent typical/atypical hyperplastic or normal breast tissue. Am. J. Clin. Pathol. 116, 129–134 (2001).

    CAS  PubMed  Article  Google Scholar 

  122. 122

    Robey, I. F. et al. Hypoxia-inducible factor-1α and the glycolytic phenotype in tumors. Neoplasia 7, 324–330 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  123. 123

    Semenza, G. L. HIF-1 and tumor progression: pathophysiology and therapeutics. Trends Mol. Med. 8, 62–67 (2002).

    Article  Google Scholar 

  124. 124

    Semenza, G. L. Targeting HIF-1 for cancer therapy. Nature Rev. Cancer 3, 721–732 (2003).

    CAS  Article  Google Scholar 

  125. 125

    Laughner, E. et al. HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1alpha (HIF-1α) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Mol. Cell Biol. 21, 3995–4004 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  126. 126

    Li, J. et al. Altered metabolic response to intermittent hypoxia in mice with partial deficiency of hypoxia-inducible factor-1α. Physiol. Genomics 25, 450–457 (2006).

    CAS  PubMed  Article  Google Scholar 

  127. 127

    Menendez, J. A . et al. 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-1α (HIF-1α)-related expression of vascular endothelial growth factor (VEGF) in cancer cells overexpressing Her-2/neu oncogene. J. Cell. Biochem. 94, 857–863 (2005).

    CAS  PubMed  Article  Google Scholar 

  128. 128

    Pflug, B. R. et al. Increased fatty acid synthase expression and activity during progression of prostate cancer in the TRAMP model. Prostate 57, 245–254 (2003).

    CAS  PubMed  Article  Google Scholar 

  129. 129

    Rossi, S. et al. Fatty acid synthase expression defines distinct molecular signatures in prostate cancer. Mol. Cancer Res. 1, 707–715 (2003).

    CAS  PubMed  Google Scholar 

  130. 130

    De Schrijver, E. et al. RNA interference-mediated silencing of the fatty acid synthase gene attenuates growth and induces morphological changes and apoptosis of LNCaP prostate cancer cells. Cancer Res. 63, 3799–3804 (2003).

    CAS  PubMed  Google Scholar 

  131. 131

    Menendez, J. A. et al. 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, 19–35 (2005). First experimental evidence demonstrating a role for FASN in the response of cancer cells to chemotherapy.

    CAS  PubMed  Article  Google Scholar 

  132. 132

    Menendez, J. A., Colomer, R. & 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, 411–422 (2004).

    CAS  PubMed  Google Scholar 

  133. 133

    Menendez, J. A., Lupu, R. & 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, 183–195 (2004).

    CAS  PubMed  Article  Google Scholar 

  134. 134

    Lu, S. & Archer, M. C. Fatty acid synthase is a potential molecular target for the chemoprevention of breast cancer. Carcinogenesis 26, 153–157 (2005).

    CAS  PubMed  Article  Google Scholar 

  135. 135

    Alli, P. M. et al. Fatty acid synthase inhibitors are chemopreventive for mammary cancer in neu-N transgenic mice. Oncogene 24, 39–46 (2005). This in vivo study supports the notion of targeting FASN as a valuable approach in breast cancer chemoprevention.

    CAS  PubMed  Article  Google Scholar 

  136. 136

    Cunningham, B. A. et al. “Spot 14” protein: a metabolic integrator in normal and neoplastic cells. Thyroid 8, 815–825 (1998).

    CAS  PubMed  Article  Google Scholar 

  137. 137

    Moncur, J. T. et al. 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. USA 95, 6989–6994 (1998).

    CAS  PubMed  Article  Google Scholar 

  138. 138

    Wells, W. A. et al. Expression of “Spot 14” (THRSP) predicts disease free survival in invasive breast cancer: immunohistochemical analysis of a new molecular marker. Breast Cancer Res. Treat. 98, 231–240 (2006).

    CAS  PubMed  Article  Google Scholar 

  139. 139

    Martel, P. M. et al. S14 protein in breast cancer cells: direct evidence of regulation by SREBP-1c, superinduction with progestin, and effects on cell growth. Exp. Cell Res. 312, 278–288 (2006).

    CAS  PubMed  Google Scholar 

  140. 140

    Kinlaw, W. B. et al. Spot 14: A marker of aggressive breast cancer and a potential therapeutic target. Endocrinology 147, 4048–4055 (2006).

    CAS  PubMed  Article  Google Scholar 

  141. 141

    Magnard, C. et al. BRCA1 interacts with acetyl-CoA carboxylase throuch its tandem of BRCT domains. Oncogene 21, 6729–6739 (2002).

    CAS  PubMed  Article  Google Scholar 

  142. 142

    Moreau, K. et al. BRCA1 affects lipid synthesis through its interaction with acetyl-CoA carboxylase. J. Biol. Chem. 281, 3172–3181 (2006). This study reveals that neoplastic lipogenesis may associate with an increased susceptibility to breast and ovarian cancer through BRCA1.

    CAS  PubMed  Article  Google Scholar 

  143. 143

    Brunet, J. et al. BRCA1 and Acetyl-CoA Carboxylase: The metabolic syndrome of breast cancer. Mol. Carcinog. 9 July 2007 [Epub ahead of print].

  144. 144

    Hardie, D. G. Minireview: the AMP-activated protein kinase cascade: the key sensor of cellular energy status. Endocrinology 144, 5179–5183 (2003).

    CAS  PubMed  Article  Google Scholar 

  145. 145

    Long, Y. C. & Zierath, J. R. AMP-activated protein kinase signaling in metabolic regulation. J. Clin. Invest. 116, 1776–1783 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  146. 146

    Luo, Z. et al. AMPK, the metabolic syndrome and cancer. Trends Pharmacol. Sci. 26, 69–76 (2005).

    CAS  PubMed  Article  Google Scholar 

  147. 147

    Swinnen, J. V. et al. Mimicry of a cellular low energy status blocks tumor cells anabolism and suppresses the malignant phenotype. Cancer Res. 65, 2441–2448 (2005). Provides clear evidence that the energy status of tumour cells is crucial in the maintenance of the transformed phenotype.

    CAS  PubMed  Article  Google Scholar 

  148. 148

    Guastamacchia, E. et al. Evidence for a putative relationship between type 2 diabetes and neoplasia with particular reference to breast cancer: Role of hormones, growth factors and specific receptors. Curr. Drug Targets Immune. Endocr. Metabol. Disord. 4, 59–66 (2004).

    CAS  PubMed  Article  Google Scholar 

  149. 149

    Resta, F. et al. The impact of body mass index and type 2 diabetes on breast cancer: current therapeutic measures of prevention. Curr. Drug Targets Immune Endocr. Metabol. Disord. 4, 327–333 (2004).

    CAS  PubMed  Article  Google Scholar 

  150. 150

    Zakikhani, M. et al. Metformin is an AMPK kinase-dependent growth inhibitor for breast cancer cells. Cancer Res. 66, 10269–10273 (2007).

    Article  Google Scholar 

  151. 151

    Pemble, C. W. IIII et al. Crystal structure of the thioesterase domain of human fatty acid synthase inhibited by Orlistat. Struct. Mol. Biol. 14, 704–709 (2007). This report should provide an excellent base from which to develop new anti-FASN agents with therapeutic value.

    CAS  Article  Google Scholar 

  152. 152

    Knowles, L. M. & Smith, J. W. Genome-wide changes accompanying knockdown of fatty acid synthase in breast cancer. BMC Genomics 8, 168 (2007).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  153. 153

    Little, J. L. et al. Inhibition of fatty acid synthase induces endoplasmic reticulum stress in tumor cells. Cancer Res. 67, 1262–1269, 2007.

    CAS  PubMed  Article  Google Scholar 

  154. 154

    Buzzai, M. et al. Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer Res. 67, 6745–6752 (2007).

    CAS  PubMed  Article  Google Scholar 

  155. 155

    Ogata, M. et al. Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol. Cell Biol. 26, 9220–9231 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  156. 156

    Yorimitsu, T. & Klionsky, D. J. Endoplasmic reticulum stress: a new pathway to induce autophagy. Autophagy 3, 160–162 (2007).

    CAS  PubMed  Article  Google Scholar 

  157. 157

    Degenhardt, K. et al. Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell. 10, 51–64 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  158. 158

    Jin, S. & White, E. Role of autophagy in cancer: management of metabolic stress. Autophagy 3, 28–31 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  159. 159

    Jin, S. et al. Metabolic catastrophe as a means to cancer cell death. J.Cell. Sci. 120, 379–378 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  160. 160

    Levine, B. Cell biology: autophagy and cancer. Nature 446, 745–747 (2007).

    CAS  Article  PubMed  Google Scholar 

  161. 161

    Rodriguez-Gonzalez, A. et al. Inhibition of choline kinase renders a highly selective cytotoxic effect in tumour cells through a mitochondrial independent mechanism. Int. J. Oncol. 26, 999–1008 (2005).

    CAS  PubMed  Google Scholar 

  162. 162

    Simons, K. & Ikonen, E. Functional rafts in cell membranes. Nature 387, 569–572 (1997).

    CAS  Article  PubMed  Google Scholar 

  163. 163

    Helms, J. B. & Zurzolo, C. Lipids as targeting signals: lipid rafts and intracellular trafficking. Traffic 5, 247–254 (2004).

    CAS  PubMed  Article  Google Scholar 

  164. 164

    Nagy, P. et al. Lipid rafts and the local density of ErbB proteins influence the biological role of homo- and heteroassociations of ErbB2. J. Cell Sci. 115, 4251–4262 (2002).

    CAS  PubMed  Article  Google Scholar 

  165. 165

    Yarden, Y. & Sliwkowski, M. X. Untangling the ErbB signalling network. Nature Rev. Mol. Cell Biol. 2, 127–137 (2001).

    CAS  Article  Google Scholar 

  166. 166

    Nahta, R. et al. Mechanisms of disease: understanding resistance to HER2-targeted therapy in human breast cancer. Nature Clin. Pract. Oncol. 3, 269–280 (2006).

    CAS  Article  Google Scholar 

  167. 167

    Xing, X. The ets protein PEA3 suppresses HER-2/neu overexpression and inhibits tumorigenesis. Nature Med. 6, 189–195 (2000).

    CAS  PubMed  Article  Google Scholar 

  168. 168

    Hurst, H. C. Update of HER-2 as a target for cancer therapy: the ERBB2 promoter and its exploitation for cancer treatment. Breast Cancer Res. 3, 395–398 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  169. 169

    Menendez, J. A. et al. 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, 2425–2432 (2006).

    CAS  PubMed  Article  Google Scholar 

  170. 170

    Citri, A. & Yarden, Y. EGF-ERBB signalling: towards the systems level. Nature Rev. Mol. Cell Biol. 7, 505–516 (2006).

    CAS  Article  Google Scholar 

  171. 171

    Menendez, J. A., Vellon, L. & Lupu, R. Orlistat: from antiobesity drug to anticancer agent in Her-2/neu (erbB-2)-overexpressing gastrointestinal tumors? Exp. Biol. Med (Maywood) 230, 151–154 (2005).

    CAS  Article  Google Scholar 

  172. 172

    Loftus, T. M. et al. Reduced food intake and body weight in mice treated with fatty acid synthase inhibitors. Science 288, 2379–2381 (2000).

    CAS  Article  Google Scholar 

  173. 173

    Wortman, M. D. et al. C75 inhibits food intake by increasing CNS glucose metabolism. Nature Med. 9, 483–485 (2003).

    CAS  PubMed  Article  Google Scholar 

  174. 174

    Wang, X. & Tian, W. Green tea epigallocatechin gallate: a natural inhibitor of fatty-acid synthase. Biochem. Biophys. Res. Commun. 288, 1200–1206 (2001).

    CAS  PubMed  Article  Google Scholar 

  175. 175

    Brusselmans, K. et al. Induction of cancer cell apoptosis by flavonoids is associated with their ability to inhibit fatty acid synthase activity. J. Biol. Chem. 280, 5636–5645 (2005).

    CAS  PubMed  Article  Google Scholar 

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Acknowledgements

We truly regret that we could not cite the work of many of our colleagues owing to space limitation. The authors are supported by funding from Instituto de Salud Carlos III (Ministerio de Sanidad y Consumo, Fondo de Investigación Sanitaria (FIS), Spain, grants CP05-00090, PI06-0778 and RD06-0020-0028) and grant BCTR0600,894 from the Susan G. Komen Breast Cancer Foundation to J.A.M. And the Extramural Funding Program of the US National Institutes of Health, RO1CA116,623, and the Breast Cancer Auxillary Program of the Evanston Northwestern Healthacare, to R.L.

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Institut Catala d'Ooncologia

Girona Biomedical Research Institute

Evanston Northwestern Healthcare

Robert H. Lurie Comprehensive Cancer Center

Glossary

β-oxidation

The process by which fats, in the form of acyl coenzyme A (CoA) molecules, are broken down in the mitochondria to generate acetyl-CoA, the entry molecule for the Krebs cycle (also known as the citric acid cycle).

Genome copy number abnormalities

Gains and losses of DNA sequences throughout the genome that associate with cancer development. Measurement of copy number variations at multiple loci simultaneously provides an important tool for studying cancer.

Multi-enzyme

A protein possessing more than one catalytic function contributed by distinct parts of a polypeptide chain (domains), by distinct subunits, or both.

Paget's disease of the vulva

A usually non-invasive adenocarcinoma of the skin on the vulva. It may be a primary lesion but in a small percentage of women an invasive cancer of the vulva is found below the area of Paget's.

Prostatic intraepithelial neoplasia (PIN) lesions

The high-grade form of PIN has been postulated to be the precursor of invasive carcinoma of the prostate. Low-grade PIN corresponds to 'very mild' to 'mild' dysplasia.

Sterol regulatory element binding protein-1c (SREBP1c)

A basic helix-loop-helix leucine zipper transcription factor that activates genes involved in the synthesis of cholesterol and fatty acids, including fatty acid synthase.

Gene-set enrichment analysis

A microarray data analysis method that uses predefined gene sets and ranks of genes to identify significant biological changes when gene expression changes in a given microarray data set are minimal or moderate.

Ductal carcinoma in situ (DCIS)

The earliest form of breast cancer, known as stage 0 (non-invasive) cancer, which stays inside the milk duct of the breast in which it started. It is not known how to predict which DCIS lesions will become invasive.

Lobular carcinoma in situ (LCIS)

An overgrowth of cells in the lobules of the breast. These cells are not likely to turn into an invasive cancer, but having them means a higher risk of getting breast cancer.

Lipid raft aggregates

Plasma membrane domains enriched with glycosphingolipids and cholesterol that are implicated in key biological processes including signal transduction, intracellular trafficking, cell polarization and cell migration. Rafts might function as platforms regulating receptor tyrosine kinase signalling pathways.

Hypoxia-inducible factor-1α (HIF1α)

Part of a dimeric transcription factor formed of α and β subunits that is involved in the hypoxia-sensitive regulation of numerous genes, including glycolytic enzymes, glucose transporters and angiogenic factors.

TRAMP

An autochthonous mouse model of prostate cancer. Various stages of progressive prostate disease can be observed in TRAMP mice, with focal adenocarcinomas developing between 10 and 20 weeks of age with 100% frequency.

Neu-N-mice

This transgenic mouse model overexpresses the non-transforming rat homologue of ERBB2 (Neu) cDNA under control of the mouse mammary tumour virus (MMTV) promoter in a mammary-specific fashion and develops spontaneous focal NEU-expressing tumours.

Endoplasmic reticulum (ER) stress

The inability of the ER to fold proteins properly. Accumulation of unfolded proteins initiates a stress response called the unfolded protein response (UPR), a set of pathways that decreases protein synthesis. Failure of the UPR to correct ER stress results in apoptosis.

Autophagy

A cell survival mechanism that is activated in response to starvation and can lead to cell death. Subcellular membranes undergo dramatic morphological changes and portions of cytoplasm are degraded.

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Menendez, J., Lupu, R. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat Rev Cancer 7, 763–777 (2007). https://doi.org/10.1038/nrc2222

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