Plant sterols as anticancer nutrients: Evidence for their role in breast cancer

Nutrients

Volumn 5, Issue 2, 2013, Pages 359-387

  Grattan, Bruce J ^a  

^a STONY BROOK UNIVERSITY MEDICAL CENTER   (United States)

Author keywords

AMPK; Beta sitosterol; Bisphosphonates; Breast cancer; Cancer; Cholesterol; Plant sterols; Statins

Indexed keywords

ALENDRONIC ACID; ANTINEOPLASTIC AGENT; BISPHOSPHONIC ACID DERIVATIVE; CAMPESTEROL; CERAMIDE; CHOLESTEROL; COUMESTROL; ESTROGEN; ESTROGEN RECEPTOR ALPHA; ESTROGEN RECEPTOR BETA; EXEMESTANE; GAMMA INTERFERON; GLUCOSE; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE KINASE; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INTERLEUKIN 2; LIVER X RECEPTOR; LIVER X RECEPTOR BETA; METFORMIN; MEVINOLIN; PAMIDRONIC ACID; PHYTOSTEROL; PROTEIN P53; SITOSTEROL; STAT3 PROTEIN; STIGMASTEROL; TAMOXIFEN; TUMOR NECROSIS FACTOR RELATED APOPTOSIS INDUCING LIGAND; UNINDEXED DRUG;

APOPTOSIS; BONE METASTASIS; BREAST CANCER; CANCER HORMONE THERAPY; CANCER INCIDENCE; CANCER INHIBITION; CANCER RISK; CHEMOPROPHYLAXIS; COLON CANCER; CYTOKINE RELEASE; DIETARY INTAKE; DRUG POTENTIATION; DRUG RESPONSE; DRUG SELECTIVITY; DRUG SENSITIVITY; ESTROGEN ACTIVITY; GLUCOSE METABOLISM; HUMAN; INFLAMMATION; LIPID ABSORPTION; LIPID METABOLISM; LUNG CANCER; MELANOMA; METASTASIS INHIBITION; NONHUMAN; OVARIECTOMY; OXIDATIVE STRESS; PROSTATE CANCER; REVIEW; RISK REDUCTION; SIGNAL TRANSDUCTION; TUMOR IMMUNITY;

EID: 84873379110     PISSN: 20726643     EISSN: None     Source Type: Journal    
DOI: 10.3390/nu5020359     Document Type: Review

References (259)

1. Willett, W.C. Diet, nutrition, and avoidable cancer. Environ. Health Perspect. 1995, 103, 165-170.
2. Hankinson, S.E.; Colditz, G.A.; Willett, W.C. Towards an integrated model for breast cancer etiology: The lifelong interplay of genes, lifestyle, and hormones. Breast Cancer Res. 2004, 6, 213-218.
3. Greenlee, H.; White, E.; Patterson, R.E.; Kristal, A.R. Supplement use among cancer survivors in the Vitamins and Lifestyle (VITAL) study cohort. J. Altern. Complement. Med. 2004, 10, 660-666.
4. Messina, M.; Hilakivi-Clarke, L. Early intake appears to be the key to the proposed protective effects of soy intake against breast cancer. Nutr. Cancer 2009, 61, 792-798.
5. Shu, X.O.; Zheng, Y.; Cai, H.; Gu, K.; Chen, Z.; Zheng, W.; Lu, W. Soy food intake and breast cancer survival. JAMA 2009, 302, 2437-2443.
6. Boffetta, P.; Couto, E.; Wichmann, J.; Ferrari, P.; Trichopoulos, D.; Bueno-de-Mesquita, H.B.; van Duijnhoven, F.J.; Buchner, F.L.; Key, T.; Boeing, H.; et al. Fruit and vegetable intake and overall cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC). J. Natl. Cancer Inst. 2010, 102, 529-537.
7. Gandini, S.; Merzenich, H.; Robertson, C.; Boyle, P. Meta-analysis of studies on breast cancer risk and diet: The role of fruit and vegetable consumption and the intake of associated micronutrients. Eur. J. Cancer 2000, 36, 636-646.
8. Aune, D.; Chan, D.S.; Vieira, A.R.; Rosenblatt, D.A.; Vieira, R.; Greenwood, D.C.; Norat, T. Fruits, vegetables and breast cancer risk: A systematic review and meta-analysis of prospective studies. Breast Cancer Res. Treat. 2012, 134, 479-493.
9. Bao, P.P.; Shu, X.O.; Zheng, Y.; Cai, H.; Ruan, Z.X.; Gu, K.; Su, Y.; Gao, Y.T.; Zheng, W.; Lu, W. Fruit, vegetable, and animal food intake and breast cancer risk by hormone receptor status. Nutr. Cancer 2012, 64, 806-819.
10. Kanematsu, S.; Yoshizawa, K.; Uehara, N.; Miki, H.; Sasaki, T.; Kuro, M.; Lai, Y.C.; Kimura, A.; Yuri, T.; Tsubura, A. Sulforaphane inhibits the growth of KPL-1 human breast cancer cells in vitro and suppresses the growth and metastasis of orthotopically transplanted KPL-1 cells in female athymic mice. Oncol. Rep. 2011, 26, 603-608.
11. Wu, Y.; Feng, X.; Jin, Y.; Wu, Z.; Hankey, W.; Paisie, C.; Li, L.; Liu, F.; Barsky, S.H.; Zhang, W.; et al. A novel mechanism of indole-3-carbinol effects on breast carcinogenesis involves induction of Cdc25A degradation. Cancer Prev. Res. (Phila.) 2010, 3, 818-828.
12. Zaineddin, A.K.; Vrieling, A.; Buck, K.; Becker, S.; Linseisen, J.; Flesch-Janys, D.; Kaaks, R.; Chang-Claude, J. Serum enterolactone and postmenopausal breast cancer risk by estrogen, progesterone and herceptin 2 receptor status. Int. J. Cancer 2011, 130, 1401-1410.
13. Torres-Sanchez, L.; Galvan-Portillo, M.; Wolff, M.S.; Lopez-Carrillo, L. Dietary consumption of phytochemicals and breast cancer risk in Mexican women. Public Health Nutr. 2009, 12, 825-831.
14. Otaegui-Arrazola, A.; Menendez-Carreno, M.; Ansorena, D.; Astiasaran, I. Oxysterols: A world to explore. Food Chem. Toxicol. 2010, 48, 3289-3303.
15. Roche, Y.; Gerbeau-Pissot, P.; Buhot, B.; Thomas, D.; Bonneau, L.; Gresti, J.; Mongrand, S.; Perrier-Cornet, J.M.; Simon-Plas, F. Depletion of phytosterols from the plant plasma membrane provides evidence for disruption of lipid rafts. FASEB J. 2008, 22, 3980-3991.
16. Weihrauch, J.L.; Gardner, J.M. Sterol content of foods of plant origin. J. Am. Diet. Assoc. 1978, 73, 39-47.
17. Ito, T.; Tamura, T.; Matsumoto, T. Sterol composition of 19 vegetable oils. J. Am. Oil Chem. Soc. 1973, 50, 122-125.
18. Amaral, J.S.; Casal, S.; Pereira, J.A.; Seabra, R.M.; Oliveira, B.P. Determination of sterol and fatty acid compositions, oxidative stability, and nutritional value of six walnut (Juglans regia L.) cultivars grown in Portugal. J. Agric. Food Chem. 2003, 51, 7698-7702.
19. Dietary Guidelines for Americans; US Department of Health and Human Services: Washington, DC, USA, 2005.
20. Ostlund, R.E., Jr. Phytosterols in human nutrition. Annu. Rev. Nutr. 2002, 22, 533-549.
21. Heinemann, T.; Axtmann, G.; von Bergmann, K. Comparison of intestinal absorption of cholesterol with different plant sterols in man. Eur. J. Clin. Invest. 1993, 23, 827-831.
22. Ostlund, R.E., Jr. Phytosterols and cholesterol metabolism. Curr. Opin. Lipidol. 2004, 15, 37-41.
23. Salen, G.; Ahrens, E.H., Jr.; Grundy, S.M. Metabolism of beta-sitosterol in man. J. Clin. Invest. 1970, 49, 952-967.
24. Ostlund, R.E., Jr.; McGill, J.B.; Zeng, C.M.; Covey, D.F.; Stearns, J.; Stenson, W.F.; Spilburg, C.A. Gastrointestinal absorption and plasma kinetics of soy Delta(5)-phytosterols and phytostanols in humans. Am. J. Physiol. Endocrinol. Metab. 2002, 282, E911-E916.
25. Bradford, P.G.; Awad, A.B. Phytosterols as anticancer compounds. Mol. Nutr. Food Res. 2007, 51, 161-170.
26. Hallikainen, M.A.; Sarkkinen, E.S.; Gylling, H.; Erkkila, A.T.; Uusitupa, M.I. Comparison of the effects of plant sterol ester and plant stanol ester-enriched margarines in lowering serum cholesterol concentrations in hypercholesterolaemic subjects on a low-fat diet. Eur. J. Clin. Nutr. 2000, 54, 715-725.
27. Weststrate, J.A.; Meijer, G.W. Plant sterol-enriched margarines and reduction of plasma total-and LDL-cholesterol concentrations in normocholesterolaemic and mildly hypercholesterolaemic subjects. Eur. J. Clin. Nutr. 1998, 52, 334-343.
28. Graf, G.A.; Li, W.P.; Gerard, R.D.; Gelissen, I.; White, A.; Cohen, J.C.; Hobbs, H.H. Coexpression of ATP-binding cassette proteins ABCG5 and ABCG8 permits their transport to the apical surface. J. Clin. Invest. 2002, 110, 659-669.
29. Yu, L.; Hammer, R.E.; Li-Hawkins, J.; von Bergmann, K.; Lutjohann, D.; Cohen, J.C.; Hobbs, H.H. Disruption of Abcg5 and Abcg8 in mice reveals their crucial role in biliary cholesterol secretion. Proc. Natl. Acad. Sci. USA 2002, 99, 16237-16242.
30. Yu, L.; Li-Hawkins, J.; Hammer, R.E.; Berge, K.E.; Horton, J.D.; Cohen, J.C.; Hobbs, H.H. Overexpression of ABCG5 and ABCG8 promotes biliary cholesterol secretion and reduces fractional absorption of dietary cholesterol. J. Clin. Invest. 2002, 110, 671-680.
31. Chan, Y.M.; Varady, K.A.; Lin, Y.; Trautwein, E.; Mensink, R.P.; Plat, J.; Jones, P.J. Plasma concentrations of plant sterols: Physiology and relationship with coronary heart disease. Nutr. Rev. 2006, 64, 385-402.
32. Messina, M.; Barnes, S. The role of soy products in reducing risk of cancer. J. Natl. Cancer Inst. 1991, 83, 541-546.
33. Cui, X.; Dai, Q.; Tseng, M.; Shu, X.O.; Gao, Y.T.; Zheng, W. Dietary patterns and breast cancer risk in the shanghai breast cancer study. Cancer Epidemiol. Biomarkers Prev. 2007, 16, 1443-1448.
34. Law, M. Plant sterol and stanol margarines and health. BMJ 2000, 320, 861-864.
35. Jones, P.J.; Raeini-Sarjaz, M. Plant sterols and their derivatives: The current spread of results. Nutr. Rev. 2001, 59, 21-24.
36. Katan, M.B.; Grundy, S.M.; Jones, P.; Law, M.; Miettinen, T.; Paoletti, R. Efficacy and safety of plant stanols and sterols in the management of blood cholesterol levels. Mayo Clin. Proc. 2003, 78, 965-978.
37. Normen, A.L.; Brants, H.A.; Voorrips, L.E.; Andersson, H.A.; van den Brandt, P.A.; Goldbohm, R.A. Plant sterol intakes and colorectal cancer risk in the Netherlands Cohort Study on Diet and Cancer. Am. J. Clin. Nutr. 2001, 74, 141-148.
38. Awad, A.B.; Fink, C.S.; Williams, H.; Kim, U. In vitro and in vivo (SCID mice) effects of phytosterols on the growth and dissemination of human prostate cancer PC-3 cells. Eur. J. Cancer Prev. 2001, 10, 507-513.
39. Baskar, A.A.; Al Numair, K.S.; Gabriel Paulraj, M.; Alsaif, M.A.; Muamar, M.A.; Ignacimuthu, S. Beta-sitosterol prevents lipid peroxidation and improves antioxidant status and histoarchitecture in rats with 1,2-dimethylhydrazine-induced colon cancer. J. Med. Food 2012, 15, 335-343.
40. Mendilaharsu, M.; de Stefani, E.; Deneo-Pellegrini, H.; Carzoglio, J.; Ronco, A. Phytosterols and risk of lung cancer: A case-control study in Uruguay. Lung Cancer 1998, 21, 37-45.
41. De Stefani, E.; Boffetta, P.; Ronco, A.L.; Brennan, P.; Deneo-Pellegrini, H.; Carzoglio, J.C.; Mendilaharsu, M. Plant sterols and risk of stomach cancer: A case-control study in Uruguay. Nutr. Cancer 2000, 37, 140-144.
42. Nair, P.P.; Turjman, N.; Kessie, G.; Calkins, B.; Goodman, G.T.; Davidovitz, H.; Nimmagadda, G. Diet, nutrition intake, and metabolism in populations at high and low risk for colon cancer. Dietary cholesterol, beta-sitosterol, and stigmasterol. Am. J. Clin. Nutr. 1984, 40, 927-930.
43. The American Institute for Cancer Research (AICR). Plant Compound Continue to Challenge Science; AICR: Washington, DC, USA, 2006.
44. Jemal, A.; Bray, F.; Center, M.M.; Ferlay, J.; Ward, E.; Forman, D. Global cancer statistics. CA Cancer J. Clin. 2011, 61, 69-90.
45. Bray, F.; McCarron, P.; Parkin, D.M. The changing global patterns of female breast cancer incidence and mortality. Breast Cancer Res. 2004, 6, 229-239.
46. Kataja, V.; Castiglione, M. Primary breast cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann. Oncol. 2009, 20, 10-14.
47. Ganry, O. Phytoestrogen and breast cancer prevention. Eur. J. Cancer Prev. 2002, 11, 519-522.
48. Signorelli, P.; Ghidoni, R. Resveratrol as an anticancer nutrient: molecular basis, open questions and promises. J. Nutr. Biochem. 2005, 16, 449-466.
49. McGuire, W.L. Steroid receptors in human breast cancer. Cancer Res. 1978, 38, 4289-4291.
50. Jordan, V.C. Progress in the prevention of breast cancer: Concept to reality. J. Steroid Biochem. Mol. Biol. 2000, 74, 269-277.
51. Begg, L.; Kuller, L.H.; Gutai, J.P.; Caggiula, A.G.; Wolmark, N.; Watson, C.G. Endogenous sex hormone levels and breast cancer risk. Genet. Epidemiol. 1987, 4, 233-247.
52. Rossouw, J.E.; Anderson, G.L.; Prentice, R.L.; LaCroix, A.Z.; Kooperberg, C.; Stefanick, M.L.; Jackson, R.D.; Beresford, S.A.; Howard, B.V.; Johnson, K.C.; et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results From the Women's Health Initiative randomized controlled trial. JAMA 2002, 288, 321-333.
53. Vogel, V.G.; Costantino, J.P.; Wickerham, D.L.; Cronin, W.M.; Cecchini, R.S.; Atkins, J.N.; Bevers, T.B.; Fehrenbacher, L.; Pajon, E.R., Jr.; Wade, J.L., III; et al. Effects of tamoxifen vs. raloxifene on the risk of developing invasive breast cancer and other disease outcomes: The NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA 2006, 295, 2727-2741.
54. Rebbeck, T.R.; Lynch, H.T.; Neuhausen, S.L.; Narod, S.A.; Van't Veer, L.; Garber, J.E.; Evans, G.; Isaacs, C.; Daly, M.B.; Matloff, E.; et al. Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N. Engl. J. Med. 2002, 346, 1616-1622.
55. Russo, J.; Hasan Lareef, M.; Balogh, G.; Guo, S.; Russo, I.H. Estrogen and its metabolites are carcinogenic agents in human breast epithelial cells. J. Steroid Biochem. Mol. Biol. 2003, 87, 1-25.
56. Fernandez, S.V.; Russo, I.H.; Russo, J. Estradiol and its metabolites 4-hydroxyestradiol and 2-hydroxyestradiol induce mutations in human breast epithelial cells. Int. J. Cancer 2006, 118, 1862-1868.
57. Mackey, R.H.; Fanelli, T.J.; Modugno, F.; Cauley, J.A.; McTigue, K.M.; Brooks, M.M.; Chlebowski, R.T.; Manson, J.E.; Klug, T.L.; Kip, K.E.; et al. Hormone therapy, estrogen metabolism, and risk of breast cancer in the women's health initiative hormone therapy trial. Cancer Epidemiol. Biomarkers Prev. 2012, 21, 2022-2032.
58. Clark, J.H. A critique of Women's Health Initiative Studies (2002-2006). Nucl. Recept. Signal. 2006, 4, e023.
59. Shapiro, S. Risks of estrogen plus progestin therapy: A sensitivity analysis of findings in the Women's Health Initiative randomized controlled trial. Climacteric 2003, 6, 302-310.
60. Machens, K.; Schmidt-Gollwitzer, K. Issues to debate on the Women's Health Initiative (WHI) study. Hormone replacement therapy: An epidemiological dilemma? Hum. Reprod. 2003, 18, 1992-1999.
61. McDonough, P.G. The randomized world is not without its imperfections: Reflections on the Women's Health Initiative Study. Fertil. Steril. 2002, 78, 951-956.
62. Goodman, N.; Goldzieher, J.W.; Ayala, C. Critique of the report from the writing group of the WHI. Menopausal Med. 2003, 10, 1-4.
63. Strom, A.; Hartman, J.; Foster, J.S.; Kietz, S.; Wimalasena, J.; Gustafsson, J.A. Estrogen receptor beta inhibits 17beta-estradiol-stimulated proliferation of the breast cancer cell line T47D. Proc. Natl. Acad. Sci. USA 2004, 101, 1566-1571.
64. Jeffy, B.D.; Hockings, J.K.; Kemp, M.Q.; Morgan, S.S.; Hager, J.A.; Beliakoff, J.; Whitesell, L.J.; Bowden, G.T.; Romagnolo, D.F. An estrogen receptor-alpha/p300 complex activates the BRCA-1 promoter at an AP-1 site that binds Jun/Fos transcription factors: Repressive effects of p53 on BRCA-1 transcription. Neoplasia 2005, 7, 873-882.
65. Goss, P.E.; Ingle, J.N.; Ales-Martinez, J.E.; Cheung, A.M.; Chlebowski, R.T.; Wactawski-Wende, J.; McTiernan, A.; Robbins, J.; Johnson, K.C.; Martin, L.W.; et al. Exemestane for breast-cancer prevention in postmenopausal women. N. Engl. J. Med. 2011, 364, 2381-2391.
66. Eckert, R.L.; Mullick, A.; Rorke, E.A.; Katzenellenbogen, B.S. Estrogen receptor synthesis and turnover in MCF-7 breast cancer cells measured by a density shift technique. Endocrinology 1984, 114, 629-637.
67. Ingram, D.; Sanders, K.; Kolybaba, M.; Lopez, D. Case-control study of phyto-oestrogens and breast cancer. Lancet 1997, 350, 990-994.
68. Paruthiyil, S.; Parmar, H.; Kerekatte, V.; Cunha, G.R.; Firestone, G.L.; Leitman, D.C. Estrogen receptor beta inhibits human breast cancer cell proliferation and tumor formation by causing a G2 cell cycle arrest. Cancer Res. 2004, 64, 423-428.
69. Rock, C.L.; Saxe, G.A.; Ruffin, M.T., IV; August, D.A.; Schottenfeld, D. Carotenoids, vitamin A, and estrogen receptor status in breast cancer. Nutr. Cancer 1996, 25, 281-296.
70. Ingram, D.M.; Roberts, A.; Nottage, E.M. Host factors and breast cancer growth characteristics. Eur. J. Cancer 1992, 28A, 1153-1161.
71. Harlan, L.C.; Coates, R.J.; Block, G.; Greenberg, R.S.; Ershow, A.; Forman, M.; Austin, D.F.; Chen, V.; Heymsfield, S.B. Estrogen receptor status and dietary intakes in breast cancer patients. Epidemiology 1993, 4, 25-31.
72. Saxe, G.A.; Rock, C.L.; Wicha, M.S.; Schottenfeld, D. Diet and risk for breast cancer recurrence and survival. Breast Cancer Res. Treat. 1999, 53, 241-253.
73. Ariazi, E.A.; Kraus, R.J.; Farrell, M.L.; Jordan, V.C.; Mertz, J.E. Estrogen-related receptor alpha1 transcriptional activities are regulated in part via the ErbB2/HER2 signaling pathway. Mol. Cancer Res. 2007, 5, 71-85.
74. Herynk, M.H.; Fuqua, S.A. Estrogen receptor mutations in human disease. Endocr. Rev. 2004, 25, 869-898.
75. Oesterreich, S.; Zhang, P.; Guler, R.L.; Sun, X.; Curran, E.M.; Welshons, W.V.; Osborne, C.K.; Lee, A.V. Re-expression of estrogen receptor alpha in estrogen receptor alpha-negative MCF-7 cells restores both estrogen and insulin-like growth factor-mediated signaling and growth. Cancer Res. 2001, 61, 5771-5777.
76. Krege, J.H.; Hodgin, J.B.; Couse, J.F.; Enmark, E.; Warner, M.; Mahler, J.F.; Sar, M.; Korach, K.S.; Gustafsson, J.A.; Smithies, O. Generation and reproductive phenotypes of mice lacking estrogen receptor beta. Proc. Natl. Acad. Sci. USA 1998, 95, 15677-15682.
77. Touillaud, M.S.; Pillow, P.C.; Jakovljevic, J.; Bondy, M.L.; Singletary, S.E.; Li, D.; Chang, S. Effect of dietary intake of phytoestrogens on estrogen receptor status in premenopausal women with breast cancer. Nutr. Cancer 2005, 51, 162-169.
78. Levi, J.A.; Wheeler, H.R. Current status of treatment for breast cancer. Ann. Acad. Med. Singap. 1990, 19, 281-285.
79. Johnston, S.R.; Head, J.; Pancholi, S.; Detre, S.; Martin, L.A.; Smith, I.E.; Dowsett, M. Integration of signal transduction inhibitors with endocrine therapy: An approach to overcoming hormone resistance in breast cancer. Clin. Cancer Res. 2003, 9, 524S-532S.
80. Gutendorf, B.; Westendorf, J. Comparison of an array of in vitro assays for the assessment of the estrogenic potential of natural and synthetic estrogens, phytoestrogens and xenoestrogens. Toxicology 2001, 166, 79-89.
81. Sakamoto, T.; Horiguchi, H.; Oguma, E.; Kayama, F. Effects of diverse dietary phytoestrogens on cell growth, cell cycle and apoptosis in estrogen-receptor-positive breast cancer cells. J. Nutr. Biochem. 2009, 21, 856-864.
82. Baker, V.A.; Hepburn, P.A.; Kennedy, S.J.; Jones, P.A.; Lea, L.J.; Sumpter, J.P.; Ashby, J. Safety evaluation of phytosterol esters. Part 1. Assessment of oestrogenicity using a combination of in vivo and in vitro assays. Food Chem. Toxicol. 1999, 37, 13-22.
83. Turnbull, D.; Frankos, V.H.; Leeman, W.R.; Jonker, D. Short-term tests of estrogenic potential of plant stanols and plant stanol esters. Regul. Toxicol. Pharmacol. 1999, 29, 211-215.
84. Malini, T.; Vanithakumari, G. Effect of beta-sitosterol on uterine biochemistry: A comparative study with estradiol and progesterone. Biochem. Mol. Biol. Int. 1993, 31, 659-668.
85. Umetani, M.; Shaul, P.W. 27-Hydroxycholesterol: the first identified endogenous SERM. Trends Endocrinol. Metab. 2011, 22, 130-135.
86. Nguyen, L.B.; Shefer, S.; Salen, G.; Tint, S.G.; Batta, A.K. Competitive inhibition of hepatic sterol 27-hydroxylase by sitosterol: Decreased activity in sitosterolemia. Proc. Assoc. Am. Physicians 1998, 110, 32-39.
87. Frasor, J.; Stossi, F.; Danes, J.M.; Komm, B.; Lyttle, C.R.; Katzenellenbogen, B.S. Selective estrogen receptor modulators: Discrimination of agonistic versus antagonistic activities by gene expression profiling in breast cancer cells. Cancer Res. 2004, 64, 1522-1533.
88. Dobs, A.S.; Schrott, H.; Davidson, M.H.; Bays, H.; Stein, E.A.; Kush, D.; Wu, M.; Mitchel, Y.; Illingworth, R.D. Effects of high-dose simvastatin on adrenal and gonadal steroidogenesis in men with hypercholesterolemia. Metabolism 2000, 49, 1234-1238.
89. Plat, J.; Nichols, J.A.; Mensink, R.P. Plant sterols and stanols: Effects on mixed micellar composition and LXR (target gene) activation. J. Lipid Res. 2005, 46, 2468-2476.
90. Song, C.; Kokontis, J.M.; Hiipakka, R.A.; Liao, S. Ubiquitous receptor: A receptor that modulates gene activation by retinoic acid and thyroid hormone receptors. Proc. Natl. Acad. Sci. USA 1994, 91, 10809-10813.
91. Seol, W.; Choi, H.S.; Moore, D.D. Isolation of proteins that interact specifically with the retinoid X receptor: Two novel orphan receptors. Mol. Endocrinol. 1995, 9, 72-85.
92. Zelcer, N.; Tontonoz, P. Liver X receptors as integrators of metabolic and inflammatory signaling. J. Clin. Invest. 2006, 116, 607-614.
93. Vedin, L.L.; Lewandowski, S.A.; Parini, P.; Gustafsson, J.A.; Steffensen, K.R. The oxysterol receptor LXR inhibits proliferation of human breast cancer cells. Carcinogenesis 2009, 30, 575-579.
94. Vigushin, D.M.; Dong, Y.; Inman, L.; Peyvandi, N.; Alao, J.P.; Sun, C.; Ali, S.; Niesor, E.J.; Bentzen, C.L.; Coombes, R.C. The nuclear oxysterol receptor LXRalpha is expressed in the normal human breast and in breast cancer. Med. Oncol. 2004, 21, 123-131.
95. Fukuchi, J.; Kokontis, J.M.; Hiipakka, R.A.; Chuu, C.P.; Liao, S. Antiproliferative effect of liver X receptor agonists on LNCaP human prostate cancer cells. Cancer Res. 2004, 64, 7686-7689.
96. Tontonoz, P.; Mangelsdorf, D.J. Liver X receptor signaling pathways in cardiovascular disease. Mol. Endocrinol. 2003, 17, 985-993.
97. Chawla, A.; Repa, J.J.; Evans, R.M.; Mangelsdorf, D.J. Nuclear receptors and lipid physiology: Opening the X-files. Science 2001, 294, 1866-1870.
98. Song, W.C. Biochemistry and reproductive endocrinology of estrogen sulfotransferase. Ann. N. Y. Acad. Sci. 2001, 948, 43-50.
99. Gong, H.; Guo, P.; Zhai, Y.; Zhou, J.; Uppal, H.; Jarzynka, M.J.; Song, W.C.; Cheng, S.Y.; Xie, W. Estrogen deprivation and inhibition of breast cancer growth in vivo through activation of the orphan nuclear receptor liver X receptor. Mol. Endocrinol. 2007, 21, 1781-1790.
100. Holm, C.; Kok, M.; Michalides, R.; Fles, R.; Koornstra, R.H.; Wesseling, J.; Hauptmann, M.; Neefjes, J.; Peterse, J.L.; Stal, O.; et al. Phosphorylation of the oestrogen receptor alpha at serine 305 and prediction of tamoxifen resistance in breast cancer. J. Pathol. 2009, 217, 372-379.
101. Kuraishy, A.; Karin, M.; Grivennikov, S.I. Tumor promotion via injury-and death-induced inflammation. Immunity 2011, 35, 467-477.
102. Lin, W.W.; Karin, M. A cytokine-mediated link between innate immunity, inflammation, and cancer. J. Clin. Invest. 2007, 117, 1175-1183.
103. Mantovani, A.; Allavena, P.; Sica, A.; Balkwill, F. Cancer-related inflammation. Nature 2008, 454, 436-444.
104. Shankaran, V.; Ikeda, H.; Bruce, A.T.; White, J.M.; Swanson, P.E.; Old, L.J.; Schreiber, R.D. IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 2001, 410, 1107-1111.
105. Schreiber, R.D.; Old, L.J.; Smyth, M.J. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science 2011, 331, 1565-1570.
106. Mahmoud, S.M.; Paish, E.C.; Powe, D.G.; Macmillan, R.D.; Grainge, M.J.; Lee, A.H.; Ellis, I.O.; Green, A.R. Tumor-infiltrating CD8+ lymphocytes predict clinical outcome in breast cancer. J. Clin. Oncol. 2011, 29, 1949-1955.
107. Liyanage, U.K.; Moore, T.T.; Joo, H.G.; Tanaka, Y.; Herrmann, V.; Doherty, G.; Drebin, J.A.; Strasberg, S.M.; Eberlein, T.J.; Goedegebuure, P.S.; Linehan, D.C. Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J. Immunol. 2002, 169, 2756-2761.
108. Beyer, M.; Schultze, J.L. Regulatory T cells in cancer. Blood 2006, 108, 804-811.
109. Breytenbach, U.; Clark, A.; Lamprecht, J.; Bouic, P. Flow cytometric analysis of the Th1-Th2 balance in healthy individuals and patients infected with the human immunodeficiency virus (HIV) receiving a plant sterol/sterolin mixture. Cell Biol. Int. 2001, 25, 43-49.
110. Qin, L.; Jin, L.; Lu, L.; Lu, X.; Zhang, C.; Zhang, F.; Liang, W. Naringenin reduces lung metastasis in a breast cancer resection model. Protein Cell 2011, 2, 507-516.
111. Calpe-Berdiel, L.; Escola-Gil, J.C.; Benitez, S.; Bancells, C.; Gonzalez-Sastre, F.; Palomer, X.; Blanco-Vaca, F. Dietary phytosterols modulate T-helper immune response but do not induce apparent anti-inflammatory effects in a mouse model of acute, aseptic inflammation. Life Sci. 2007, 80, 1951-1956.
112. Bouic, P.J.; Etsebeth, S.; Liebenberg, R.W.; Albrecht, C.F.; Pegel, K.; van Jaarsveld, P.P. Beta-sitosterol and beta-sitosterol glucoside stimulate human peripheral blood lymphocyte proliferation: Implications for their use as an immunomodulatory vitamin combination. Int. J. Immunopharmacol. 1996, 18, 693-700.
113. Imanaka, H.; Koide, H.; Shimizu, K.; Asai, T.; Kinouchi Shimizu, N.; Ishikado, A.; Makino, T.; Oku, N. Chemoprevention of tumor metastasis by liposomal beta-sitosterol intake. Biol. Pharm. Bull. 2008, 31, 400-404.
114. Turkson, J.; Bowman, T.; Garcia, R.; Caldenhoven, E.; de Groot, R.P.; Jove, R. Stat3 activation by Src induces specific gene regulation and is required for cell transformation. Mol. Cell. Biol. 1998, 18, 2545-2552.
115. Bromberg, J.F.; Horvath, C.M.; Besser, D.; Lathem, W.W.; Darnell, J.E., Jr. Stat3 activation is required for cellular transformation by v-src. Mol. Cell. Biol. 1998, 18, 2553-2558.
116. Bromberg, J.F.; Wrzeszczynska, M.H.; Devgan, G.; Zhao, Y.; Pestell, R.G.; Albanese, C.; Darnell, J.E., Jr. Stat3 as an oncogene. Cell 1999, 98, 295-303.
117. Bhardwaj, A.; Sethi, G.; Vadhan-Raj, S.; Bueso-Ramos, C.; Takada, Y.; Gaur, U.; Nair, A.S.; Shishodia, S.; Aggarwal, B.B. Resveratrol inhibits proliferation, induces apoptosis, and overcomes chemoresistance through down-regulation of STAT3 and nuclear factor-kappaB-regulated antiapoptotic and cell survival gene products in human multiple myeloma cells. Blood 2007, 109, 2293-2302.
118. Garcia, R.; Yu, C.L.; Hudnall, A.; Catlett, R.; Nelson, K.L.; Smithgall, T.; Fujita, D.J.; Ethier, S.P.; Jove, R. Constitutive activation of Stat3 in fibroblasts transformed by diverse oncoproteins and in breast carcinoma cells. Cell Growth Differ. 1997, 8, 1267-1276.
119. Turkson, J.; Jove, R. STAT proteins: Novel molecular targets for cancer drug discovery. Oncogene 2000, 19, 6613-6626.
120. Hu, X.; Chen, J.; Wang, L.; Ivashkiv, L.B. Crosstalk among Jak-STAT, Toll-like receptor, and ITAM-dependent pathways in macrophage activation. J. Leukoc. Biol. 2007, 82, 237-243.
121. Miettinen, M.; Lehtonen, A.; Julkunen, I.; Matikainen, S. Lactobacilli and Streptococci activate NF-kappa B and STAT signaling pathways in human macrophages. J. Immunol. 2000, 164, 3733-3740.
122. Sareila, O.; Hamalainen, M.; Nissinen, E.; Kankaanranta, H.; Moilanen, E. Orazipone inhibits activation of inflammatory transcription factors nuclear factor-kappa B and signal transducer and activator of transcription 1 and decreases inducible nitric-oxide synthase expression and nitric oxide production in response to inflammatory stimuli. J. Pharmacol. Exp. Ther. 2008, 324, 858-866.
123. Lo, H.W.; Hsu, S.C.; Xia, W.; Cao, X.; Shih, J.Y.; Wei, Y.; Abbruzzese, J.L.; Hortobagyi, G.N.; Hung, M.C. Epidermal growth factor receptor cooperates with signal transducer and activator of transcription 3 to induce epithelial-mesenchymal transition in cancer cells via up-regulation of TWIST gene expression. Cancer Res. 2007, 67, 9066-9076.
124. Chan, S.K.; Hill, M.E.; Gullick, W.J. The role of the epidermal growth factor receptor in breast cancer. J. Mammary Gland. Biol. Neoplasia 2006, 11, 3-11.
125. Nicholson, R.I.; Gee, J.M.; Harper, M.E. EGFR and cancer prognosis. Eur. J. Cancer 2001, 37, S9-S15.
126. Klijn, J.G.; Berns, P.M.; Schmitz, P.I.; Foekens, J.A. The clinical significance of epidermal growth factor receptor (EGF-R) in human breast cancer: A review on 5232 patients. Endocr. Rev. 1992, 13, 3-17.
127. Levin, E.R. Bidirectional signaling between the estrogen receptor and the epidermal growth factor receptor. Mol. Endocrinol. 2003, 17, 309-317.
128. Kari, C.; Chan, T.O.; Rocha de Quadros, M.; Rodeck, U. Targeting the epidermal growth factor receptor in cancer: Apoptosis takes center stage. Cancer Res. 2003, 63, 1-5.
129. Xia, W.; Lau, Y.K.; Zhang, H.Z.; Xiao, F.Y.; Johnston, D.A.; Liu, A.R.; Li, L.; Katz, R.L.; Hung, M.C. Combination of EGFR, HER-2/neu, and HER-3 is a stronger predictor for the outcome of oral squamous cell carcinoma than any individual family members. Clin. Cancer Res. 1999, 5, 4164-4174.
130. Gonzalez-Angulo, A.M.; Hortobagyi, G.N.; Esteva, F.J. Adjuvant therapy with trastuzumab for HER-2/neu-positive breast cancer. Oncologist 2006, 11, 857-867.
131. Srinivasan, V.; Spence, D.W.; Pandi-Perumal, S.R.; Trakht, I.; Esquifino, A.I.; Cardinali, D.P.; Maestroni, G.J. Melatonin, environmental light, and breast cancer. Breast Cancer Res. Treat. 2008, 108, 339-350.
132. Lollini, P.L.; Nicoletti, G.; Landuzzi, L.; de Giovanni, C.; Rossi, I.; di Carlo, E.; Musiani, P.; Muller, W.J.; Nanni, P. Down regulation of major histocompatibility complex class I expression in mammary carcinoma of HER-2/neu transgenic mice. Int. J. Cancer 1998, 77, 937-941.
133. Herrmann, F.; Lehr, H.A.; Drexler, I.; Sutter, G.; Hengstler, J.; Wollscheid, U.; Seliger, B. HER-2/neu-mediated regulation of components of the MHC class I antigen-processing pathway. Cancer Res. 2004, 64, 215-220.
134. Oliveras-Ferraros, C.; Cufi, S.; Vazquez-Martin, A.; Menendez, O.J.; Bosch-Barrera, J.; Martin-Castillo, B.; Joven, J.; Menendez, J.A. Metformin rescues cell surface major histocompatibility complex class I (MHC-I) deficiency caused by oncogenic transformation. Cell Cycle 2012, 11, 865-870.
135. Valerio, M.; Awad, A.B. Beta-Sitosterol down-regulates some pro-inflammatory signal transduction pathways by increasing the activity of tyrosine phosphatase SHP-1 in J774A.1 murine macrophages. Int. Immunopharmacol. 2011, 11, 1012-1017.
136. Nakshatri, H.; Bhat-Nakshatri, P.; Martin, D.A.; Goulet, R.J., Jr.; Sledge, G.W., Jr. Constitutive activation of NF-kappaB during progression of breast cancer to hormone-independent growth. Mol. Cell. Biol. 1997, 17, 3629-3639.
137. Uzzo, R.G.; Leavis, P.; Hatch, W.; Gabai, V.L.; Dulin, N.; Zvartau, N.; Kolenko, V.M. Zinc inhibits nuclear factor-kappa B activation and sensitizes prostate cancer cells to cytotoxic agents. Clin. Cancer Res. 2002, 8, 3579-3583.
138. Muenchen, H.J.; Lin, D.L.; Walsh, M.A.; Keller, E.T.; Pienta, K.J. Tumor necrosis factor-alpha-induced apoptosis in prostate cancer cells through inhibition of nuclear factor-kappaB by an IkappaBalpha "super-repressor". Clin. Cancer Res. 2000, 6, 1969-1977.
139. Huang, S.; Pettaway, C.A.; Uehara, H.; Bucana, C.D.; Fidler, I.J. Blockade of NF-kappaB activity in human prostate cancer cells is associated with suppression of angiogenesis, invasion, and metastasis. Oncogene 2001, 20, 4188-4197.
140. Uzzo, R.G.; Crispen, P.L.; Golovine, K.; Makhov, P.; Horwitz, E.M.; Kolenko, V.M. Diverse effects of zinc on NF-kappaB and AP-1 transcription factors: implications for prostate cancer progression. Carcinogenesis 2006, 27, 1980-1990.
141. Jesch, E.D.; Seo, J.M.; Carr, T.P.; Lee, J.Y. Sitosterol reduces messenger RNA and protein expression levels of Niemann-Pick C1-like 1 in FHs 74 Int cells. Nutr. Res. 2009, 29, 859-866.
142. Awad, A.B.; Downie, A.C.; Fink, C.S. Inhibition of growth and stimulation of apoptosis by beta-sitosterol treatment of MDA-MB-231 human breast cancer cells in culture. Int. J. Mol. Med. 2000, 5, 541-545.
143. Awad, A.B.; Barta, S.L.; Fink, C.S.; Bradford, P.G. beta-Sitosterol enhances tamoxifen effectiveness on breast cancer cells by affecting ceramide metabolism. Mol. Nutr. Food Res. 2008, 52, 419-426.
144. Awad, A.B.; Williams, H.; Fink, C.S. Effect of phytosterols on cholesterol metabolism and MAP kinase in MDA-MB-231 human breast cancer cells. J. Nutr. Biochem. 2003, 14, 111-119.
145. Pollak, O.J. Reduction of blood cholesterol in man. Circulation 1953, 7, 702-706.
146. Hinds, M.W.; Kolonel, L.N.; Lee, J.; Hankin, J.H. Dietary cholesterol and lung cancer risk among men in Hawaii. Am. J. Clin. Nutr. 1983, 37, 192-193.
147. Kitahara, C.M.; Berrington de Gonzalez, A.; Freedman, N.D.; Huxley, R.; Mok, Y.; Jee, S.H.; Samet, J.M. Total cholesterol and cancer risk in a large prospective study in Korea. J. Clin. Oncol. 2011, 29, 1592-1598.
148. Jafri, H.; Alsheikh-Ali, A.A.; Karas, R.H. Baseline and on-treatment high-density lipoprotein cholesterol and the risk of cancer in randomized controlled trials of lipid-altering therapy. J. Am. Coll. Cardiol. 2010, 55, 2846-2854.
149. Demonty, I.; Ras, R.T.; van der Knaap, H.C.; Duchateau, G.S.; Meijer, L.; Zock, P.L.; Geleijnse, J.M.; Trautwein, E.A. Continuous dose-response relationship of the LDL-cholesterol-lowering effect of phytosterol intake. J. Nutr. 2009, 139, 271-284.
150. Law, M.R.; Wald, N.J.; Rudnicka, A.R. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: Systematic review and meta-analysis. BMJ 2003, 326, 1423.
151. Graaf, M.R.; Beiderbeck, A.B.; Egberts, A.C.; Richel, D.J.; Guchelaar, H.J. The risk of cancer in users of statins. J. Clin. Oncol. 2004, 22, 2388-2394.
152. Poynter, J.N.; Gruber, S.B.; Higgins, P.D.; Almog, R.; Bonner, J.D.; Rennert, H.S.; Low, M.; Greenson, J.K.; Rennert, G. Statins and the risk of colorectal cancer. N. Engl. J. Med. 2005, 352, 2184-2192.
153. Lau, V.W.; Journoud, M.; Jones, P.J. Plant sterols are efficacious in lowering plasma LDL and non-HDL cholesterol in hypercholesterolemic type 2 diabetic and nondiabetic persons. Am. J. Clin. Nutr. 2005, 81, 1351-1358.
154. Ahn, J.; Lim, U.; Weinstein, S.J.; Schatzkin, A.; Hayes, R.B.; Virtamo, J.; Albanes, D. Prediagnostic total and high-density lipoprotein cholesterol and risk of cancer. Cancer Epidemiol. Biomarkers Prev. 2009, 18, 2814-2821.
155. Chen, H.W. Role of cholesterol metabolism in cell growth. Fed. Proc. 1984, 43, 126-130.
156. Kim, S.; Han, J.; Lee, D.H.; Cho, K.H.; Kim, K.H.; Chung, J.H. Cholesterol, a major component of caveolae, down-regulates matrix metalloproteinase-1 expression through ERK/JNK pathway in cultured human dermal fibroblasts. Ann. Dermatol. 2010, 22, 379-388.
157. Kulic, A.; Dedic Plavetic, N.; Vrbanec, J.; Sirotkovic-Skerlev, M. Low serum MMP-1 in breast cancer: A negative prognostic factor? Biomarkers 2012, 17, 416-421.
158. Brown, M.S.; Goldstein, J.L. Suppression of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and inhibition of growth of human fibroblasts by 7-ketocholesterol. J. Biol. Chem. 1974, 249, 7306-7314.
159. Chen, H.W.; Kandutsch, A.A.; Waymouth, C. Inhibition of cell growth by oxygenated derivatives of cholesterol. Nature 1974, 251, 419-421.
160. Chen, H.W.; Heiniger, H.J.; Kandutsch, A.A. Relationship between sterol synthesis and DNA synthesis in phytohemagglutinin-stimulated mouse lymphocytes. Proc. Natl. Acad. Sci. USA 1975, 72, 1950-1954.
161. Keyomarsi, K.; Sandoval, L.; Band, V.; Pardee, A.B. Synchronization of tumor and normal cells from G1 to multiple cell cycles by lovastatin. Cancer Res. 1991, 51, 3602-3609.
162. Campbell, M.J.; Esserman, L.J.; Zhou, Y.; Shoemaker, M.; Lobo, M.; Borman, E.; Baehner, F.; Kumar, A.S.; Adduci, K.; Marx, C.; et al. Breast cancer growth prevention by statins. Cancer Res. 2006, 66, 8707-8714.
163. Kumar, A.S.; Benz, C.C.; Shim, V.; Minami, C.A.; Moore, D.H.; Esserman, L.J. Estrogen receptor-negative breast cancer is less likely to arise among lipophilic statin users. Cancer Epidemiol. Biomarkers Prev. 2008, 17, 1028-1033.
164. Klawitter, J.; Shokati, T.; Moll, V.; Christians, U. Effects of lovastatin on breast cancer cells: A proteo-metabonomic study. Breast Cancer Res. 2010, 12, R16.
165. Brown, M.S.; Goldstein, J.L. The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell 1997, 89, 331-340.
166. Brown, A.J.; Sun, L.; Feramisco, J.D.; Brown, M.S.; Goldstein, J.L. Cholesterol addition to ER membranes alters conformation of SCAP, the SREBP escort protein that regulates cholesterol metabolism. Mol. Cell 2002, 10, 237-245.
167. Eberle, D.; Hegarty, B.; Bossard, P.; Ferre, P.; Foufelle, F. SREBP transcription factors: Master regulators of lipid homeostasis. Biochimie 2004, 86, 839-848.
168. Martinez-Botas, J.; Suarez, Y.; Ferruelo, A.J.; Gomez-Coronado, D.; Lasuncion, M.A. Cholesterol starvation decreases p34(cdc2) kinase activity and arrests the cell cycle at G2. FASEB J. 1999, 13, 1359-1370.
169. Newcomb, P.A.; Trentham-Dietz, A.; Hampton, J.M. Bisphosphonates for osteoporosis treatment are associated with reduced breast cancer risk. Br. J. Cancer 2010, 102, 799-802.
170. Gnant, M.; Mlineritsch, B.; Schippinger, W.; Luschin-Ebengreuth, G.; Postlberger, S.; Menzel, C.; Jakesz, R.; Seifert, M.; Hubalek, M.; Bjelic-Radisic, V.; et al. Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N. Engl. J. Med. 2009, 360, 679-691.
171. Diel, I.J.; Solomayer, E.F.; Costa, S.D.; Gollan, C.; Goerner, R.; Wallwiener, D.; Kaufmann, M.; Bastert, G. Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N. Engl. J. Med. 1998, 339, 357-363.
172. Amin, D.; Cornell, S.A.; Gustafson, S.K.; Needle, S.J.; Ullrich, J.W.; Bilder, G.E.; Perrone, M.H. Bisphosphonates used for the treatment of bone disorders inhibit squalene synthase and cholesterol biosynthesis. J. Lipid Res. 1992, 33, 1657-1663.
173. Wu, Y.W.; Oesterlin, L.K.; Tan, K.T.; Waldmann, H.; Alexandrov, K.; Goody, R.S. Membrane targeting mechanism of Rab GTPases elucidated by semisynthetic protein probes. Nat. Chem. Biol. 2010, 6, 534-540.
174. Zerial, M.; McBride, H. Rab proteins as membrane organizers. Nat. Rev. Mol. Cell. Biol. 2001, 2, 107-117.
175. Schroder, M.; Kaufman, R.J. The mammalian unfolded protein response. Annu. Rev. Biochem. 2005, 74, 739-789.
176. Kim, I.; Xu, W.; Reed, J.C. Cell death and endoplasmic reticulum stress: Disease relevance and therapeutic opportunities. Nat. Rev. Drug Discov. 2008, 7, 1013-1030.
177. Marinangeli, C.P.; Varady, K.A.; Jones, P.J. Plant sterols combined with exercise for the treatment of hypercholesterolemia: Overview of independent and synergistic mechanisms of action. J. Nutr. Biochem. 2006, 17, 217-224.
178. Tas, F.; Hansel, H.; Belce, A.; Ilvan, S.; Argon, A.; Camlica, H.; Topuz, E. Oxidative stress in breast cancer. Med. Oncol. 2005, 22, 11-15.
179. Portakal, O.; Ozkaya, O.; Erden Inal, M.; Bozan, B.; Kosan, M.; Sayek, I. Coenzyme Q10 concentrations and antioxidant status in tissues of breast cancer patients. Clin. Biochem. 2000, 33, 279-284.
180. Nagulu, M. Oxidative Stress and Anti-Oxidant Status in Breast Cancer Patients. J. Pharm. Res. 2009, 2, 62-65.
181. Vivancos, M.; Moreno, J.J. Beta-Sitosterol modulates antioxidant enzyme response in RAW 264.7 macrophages. Free Radic. Biol. Med. 2005, 39, 91-97.
182. Li, C.R.; Zhou, Z.; Lin, R.X.; Zhu, D.; Sun, Y.N.; Tian, L.L.; Li, L.; Gao, Y.; Wang, S.Q. Beta-sitosterol decreases irradiation-induced thymocyte early damage by regulation of the intracellular redox balance and maintenance of mitochondrial membrane stability. J. Cell. Biochem. 2007, 102, 748-758.
183. Gupta, R.; Sharma, A.K.; Dobhal, M.P.; Sharma, M.C.; Gupta, R.S. Antidiabetic and antioxidant potential of beta-sitosterol in streptozotocin-induced experimental hyperglycemia. J. Diabetes 2011, 3, 29-37.
184. Field, F.J.; Born, E.; Mathur, S.N. Effect of micellar beta-sitosterol on cholesterol metabolism in CaCo-2 cells. J. Lipid Res. 1997, 38, 348-360.
185. Piechota-Polanczyk, A.; Goraca, A.; Demyanets, S.; Mittlboeck, M.; Domenig, C.; Neumayer, C.; Wojta, J.; Nanobachvili, J.; Huk, I.; Klinger, M. Simvastatin decreases free radicals formation in the human abdominal aortic aneurysm wall via NF-kappaB. Eur. J. Vasc. Endovasc. Surg. 2012, 44, 133-137.
186. Bu, D.X.; Erl, W.; de Martin, R.; Hansson, G.K.; Yan, Z.Q. IKKbeta-dependent NF-kappaB pathway controls vascular inflammation and intimal hyperplasia. FASEB J. 2005, 19, 1293-1295.
187. Warburg, O. On the origin of cancer cells. Science 1956, 123, 309-314.
188. Menendez, J.A. Metformin is synthetically lethal with glucose withdrawal in cancer cells. Cell Cycle 2012, 11, 2782-2792.
189. Charni, S.; de Bettignies, G.; Rathore, M.G.; Aguilo, J.I.; van den Elsen, P.J.; Haouzi, D.; Hipskind, R.A.; Enriquez, J.A.; Sanchez-Beato, M.; Pardo, J.; et al. Oxidative phosphorylation induces de novo expression of the MHC class I in tumor cells through the ERK5 pathway. J. Immunol. 2010, 185, 3498-3503.
190. Hardie, D.G. AMPK: A key regulator of energy balance in the single cell and the whole organism. Int. J. Obes. (Lond.) 2008, 32, S7-S12.
191. Hardie, D.G. New roles for the LKB1→AMPK pathway. Curr. Opin. Cell. Biol. 2005, 17, 167-173.
192. Hardie, D.G. The AMP-activated protein kinase pathway-New players upstream and downstream. J. Cell Sci. 2004, 117, 5479-5487.
193. Towler, M.C.; Hardie, D.G. AMP-activated protein kinase in metabolic control and insulin signaling. Circ. Res. 2007, 100, 328-341.
194. Miller, R.A.; Birnbaum, M.J. An energetic tale of AMPK-independent effects of metformin. J. Clin. Invest. 2010, 120, 2267-2270.
195. Adams, J.; Chen, Z.P.; van Denderen, B.J.; Morton, C.J.; Parker, M.W.; Witters, L.A.; Stapleton, D.; Kemp, B.E. Intrasteric control of AMPK via the gamma1 subunit AMP allosteric regulatory site. Protein Sci. 2004, 13, 155-165.
196. Zhu, Z.; Jiang, W.; Thompson, M.D.; McGinley, J.N.; Thompson, H.J. Metformin as an energy restriction mimetic agent for breast cancer prevention. J. Carcinog. 2011, 10, 17.
197. Sutherland, W.H.; Scott, R.S.; Lintott, C.J.; Robertson, M.C.; Stapely, S.A.; Cox, C. Plasma non-cholesterol sterols in patients with non-insulin dependent diabetes mellitus. Horm. Metab. Res. 1992, 24, 172-175.
198. Ivorra, M.D.; D'Ocon, M.P.; Paya, M.; Villar, A. Antihyperglycemic and insulin-releasing effects of beta-sitosterol 3-beta-D-glucoside and its aglycone, beta-sitosterol. Arch. Int. Pharmacodyn. Ther. 1988, 296, 224-231.
199. Hwang, S.L.; Kim, H.N.; Jung, H.H.; Kim, J.E.; Choi, D.K.; Hur, J.M.; Lee, J.Y.; Song, H.; Song, K.S.; Huh, T.L. Beneficial effects of beta-sitosterol on glucose and lipid metabolism in L6 myotube cells are mediated by AMP-activated protein kinase. Biochem. Biophys. Res. Commun. 2008, 377, 1253-1258.
200. Habegger, K.M.; Penque, B.A.; Sealls, W.; Tackett, L.; Bell, L.N.; Blue, E.K.; Gallagher, P.J.; Sturek, M.; Alloosh, M.A.; Steinberg, H.O.; et al. Fat-induced membrane cholesterol accrual provokes cortical filamentous actin destabilisation and glucose transport dysfunction in skeletal muscle. Diabetologia 2011, 55, 457-467.
201. Looije, N.A.; Risovic, V.; Stewart, D.J.; Debeyer, D.; Kutney, J.; Wasan, K.M. Disodium Ascorbyl Phytostanyl Phosphates (FM-VP4) reduces plasma cholesterol concentration, body weight and abdominal fat gain within a dietary-induced obese mouse model. J. Pharm. Pharm. Sci. 2005, 8, 400-408.
202. Kritchevsky, D. Caloric restriction and cancer. J. Nutr. Sci. Vitaminol. (Tokyo) 2001, 47, 13-19.
203. Thompson, H.J.; Zhu, Z.; Jiang, W. Dietary energy restriction in breast cancer prevention. J. Mammary Gland. Biol. Neoplasia 2003, 8, 133-142.
204. Carling, D.; Zammit, V.A.; Hardie, D.G. A common bicyclic protein kinase cascade inactivates the regulatory enzymes of fatty acid and cholesterol biosynthesis. FEBS Lett. 1987, 223, 217-222.
205. Jones, R.G.; Plas, D.R.; Kubek, S.; Buzzai, M.; Mu, J.; Xu, Y.; Birnbaum, M.J.; Thompson, C.B. AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol. Cell 2005, 18, 283-293.
206. Levine, A.J. p53, the cellular gatekeeper for growth and division. Cell 1997, 88, 323-331.
207. Hollstein, M.; Sidransky, D.; Vogelstein, B.; Harris, C.C. p53 mutations in human cancers. Science 1991, 253, 49-53.
208. Freed-Pastor, W.A.; Mizuno, H.; Zhao, X.; Langerod, A.; Moon, S.H.; Rodriguez-Barrueco, R.; Barsotti, A.; Chicas, A.; Li, W.; Polotskaia, A.; et al. Mutant p53 disrupts mammary tissue architecture via the mevalonate pathway. Cell 2012, 148, 244-258.
209. Perens, E.A.; Shaham, S. C. elegans daf-6 encodes a patched-related protein required for lumen formation. Dev. Cell 2005, 8, 893-906.
210. Tullet, J.M.; Hertweck, M.; An, J.H.; Baker, J.; Hwang, J.Y.; Liu, S.; Oliveira, R.P.; Baumeister, R.; Blackwell, T.K. Direct inhibition of the longevity-promoting factor SKN-1 by insulin-like signaling in C. elegans. Cell 2008, 132, 1025-1038.
211. Greer, E.L.; Banko, M.R.; Brunet, A. AMP-activated protein kinase and FoxO transcription factors in dietary restriction-induced longevity. Ann. N. Y. Acad. Sci. 2009, 1170, 688-692.
212. Mauro, C.; Crescenzi, E.; de Mattia, R.; Pacifico, F.; Mellone, S.; Salzano, S.; de Luca, C.; D'Adamio, L.; Palumbo, G.; Formisano, S.; et al. Central role of the scaffold protein tumor necrosis factor receptor-associated factor 2 in regulating endoplasmic reticulum stress-induced apoptosis. J. Biol. Chem. 2006, 281, 2631-2638.
213. Cowey, S.; Hardy, R.W. The metabolic syndrome: A high-risk state for cancer? Am. J. Pathol. 2006, 169, 1505-1522.
214. Kaaks, R.; Lukanova, A. Energy balance and cancer: The role of insulin and insulin-like growth factor-I. Proc. Nutr. Soc. 2001, 60, 91-106.
215. Golden, S.H.; Dobs, A.S.; Vaidya, D.; Szklo, M.; Gapstur, S.; Kopp, P.; Liu, K.; Ouyang, P. Endogenous sex hormones and glucose tolerance status in postmenopausal women. J. Clin. Endocrinol. Metab. 2007, 92, 1289-1295.
216. Giovannucci, E.; Harlan, D.M.; Archer, M.C.; Bergenstal, R.M.; Gapstur, S.M.; Habel, L.A.; Pollak, M.; Regensteiner, J.G.; Yee, D. Diabetes and cancer: A consensus report. Diabetes Care 2010, 33, 1674-1685.
217. Dupont, J.; Karas, M.; LeRoith, D. The potentiation of estrogen on insulin-like growth factor I action in MCF-7 human breast cancer cells includes cell cycle components. J. Biol. Chem. 2000, 275, 35893-35901.
218. Brodt, P.; Samani, A.; Navab, R. Inhibition of the type I insulin-like growth factor receptor expression and signaling: Novel strategies for antimetastatic therapy. Biochem. Pharmacol. 2000, 60, 1101-1107.
219. Peres, C.; Yart, A.; Perret, B.; Salles, J.P.; Raynal, P. Modulation of phosphoinositide 3-kinase activation by cholesterol level suggests a novel positive role for lipid rafts in lysophosphatidic acid signalling. FEBS Lett. 2003, 534, 164-168.
220. Irwin, M.E.; Bohin, N.; Boerner, J.L. Src family kinases mediate epidermal growth factor receptor signaling from lipid rafts in breast cancer cells. Cancer Biol. Ther. 2011, 12, 718-726.
221. Brown, D.A. Lipid rafts, detergent-resistant membranes, and raft targeting signals. Physiology (Bethesda) 2006, 21, 430-439.
222. Ogretmen, B.; Hannun, Y.A. Biologically active sphingolipids in cancer pathogenesis and treatment. Nat. Rev. Cancer 2004, 4, 604-616.
223. Yu, C.; Alterman, M.; Dobrowsky, R.T. Ceramide displaces cholesterol from lipid rafts and decreases the association of the cholesterol binding protein caveolin-1. J. Lipid Res. 2005, 46, 1678-1691.
224. Hajduch, E.; Turban, S.; le Liepvre, X.; le Lay, S.; Lipina, C.; Dimopoulos, N.; Dugail, I.; Hundal, H.S. Targeting of PKCzeta and PKB to caveolin-enriched microdomains represents a crucial step underpinning the disruption in PKB-directed signalling by ceramide. Biochem. J. 2008, 410, 369-379.
225. Jiang, B.H.; Liu, L.Z. PI3K/PTEN signaling in tumorigenesis and angiogenesis. Biochim. Biophys. Acta 2008, 1784, 150-158.
226. Haimovitz-Friedman, A.; Kan, C.C.; Ehleiter, D.; Persaud, R.S.; McLoughlin, M.; Fuks, Z.; Kolesnick, R.N. Ionizing radiation acts on cellular membranes to generate ceramide and initiate apoptosis. J. Exp. Med. 1994, 180, 525-535.
227. Von Haefen, C.; Wieder, T.; Gillissen, B.; Starck, L.; Graupner, V.; Dorken, B.; Daniel, P.T. Ceramide induces mitochondrial activation and apoptosis via a Bax-dependent pathway in human carcinoma cells. Oncogene 2002, 21, 4009-4019.
228. Awad, A.B.; von Holtz, R.L.; Cone, J.P.; Fink, C.S.; Chen, Y.C. Beta-sitosterol inhibits growth of HT-29 human colon cancer cells by activating the sphingomyelin cycle. Anticancer Res. 1998, 18, 471-473.
229. Senchenkov, A.; Litvak, D.A.; Cabot, M.C. Targeting ceramide metabolism-A strategy for overcoming drug resistance. J. Natl. Cancer Inst. 2001, 93, 347-357.
230. Liu, Y.Y.; Han, T.Y.; Giuliano, A.E.; Cabot, M.C. Expression of glucosylceramide synthase, converting ceramide to glucosylceramide, confers adriamycin resistance in human breast cancer cells. J. Biol. Chem. 1999, 274, 1140-1146.
231. Lucci, A.; Cho, W.I.; Han, T.Y.; Giuliano, A.E.; Morton, D.L.; Cabot, M.C. Glucosylceramide: A marker for multiple-drug resistant cancers. Anticancer Res. 1998, 18, 475-480.
232. Zhang, X.; Li, J.; Qiu, Z.; Gao, P.; Wu, X.; Zhou, G. Co-suppression of MDR1 (multidrug resistance 1) and GCS (glucosylceramide synthase) restores sensitivity to multidrug resistance breast cancer cells by RNA interference (RNAi). Cancer Biol. Ther. 2009, 8, 1117-1121.
233. Zhang, X.; Wu, X.; Li, J.; Sun, Y.; Gao, P.; Zhang, C.; Zhang, H.; Zhou, G. MDR1 (multidrug resistence 1) can regulate GCS (glucosylceramide synthase) in breast cancer cells. J. Surg. Oncol. 2011, 104, 466-471.
234. Lavie, Y.; Cao, H.; Volner, A.; Lucci, A.; Han, T.Y.; Geffen, V.; Giuliano, A.E.; Cabot, M.C. Agents that reverse multidrug resistance, tamoxifen, verapamil, and cyclosporin A, block glycosphingolipid metabolism by inhibiting ceramide glycosylation in human cancer cells. J. Biol. Chem. 1997, 272, 1682-1687.
235. Lavie, Y.; Fiucci, G.; Liscovitch, M. Up-regulation of caveolae and caveolar constituents in multidrug-resistant cancer cells. J. Biol. Chem. 1998, 273, 32380-32383.
236. Daniel, E.E.; El-Yazbi, A.; Cho, W.J. Caveolae and calcium handling, a review and a hypothesis. J. Cell. Mol. Med. 2006, 10, 529-544.
237. Galbiati, F.; Volonte, D.; Liu, J.; Capozza, F.; Frank, P.G.; Zhu, L.; Pestell, R.G.; Lisanti, M.P. Caveolin-1 expression negatively regulates cell cycle progression by inducing G(0)/G(1) arrest via a p53/p21(WAF1/Cip1)-dependent mechanism. Mol. Biol. Cell. 2001, 12, 2229-2244.
238. Schlegel, A.; Wang, C.; Pestell, R.G.; Lisanti, M.P. Ligand-independent activation of oestrogen receptor alpha by caveolin-1. Biochem. J. 2001, 359, 203-210.
239. Mineo, C.; James, G.L.; Smart, E.J.; Anderson, R.G. Localization of epidermal growth factor-stimulated Ras/Raf-1 interaction to caveolae membrane. J. Biol. Chem. 1996, 271, 11930-11935.
240. Li, S.; Couet, J.; Lisanti, M.P. Src tyrosine kinases, Galpha subunits, and H-Ras share a common membrane-anchored scaffolding protein, caveolin. Caveolin binding negatively regulates the auto-activation of Src tyrosine kinases. J. Biol. Chem. 1996, 271, 29182-29190.
241. Gustavsson, J.; Parpal, S.; Karlsson, M.; Ramsing, C.; Thorn, H.; Borg, M.; Lindroth, M.; Peterson, K.H.; Magnusson, K.E.; Stralfors, P. Localization of the insulin receptor in caveolae of adipocyte plasma membrane. FASEB J. 1999, 13, 1961-1971.
242. Parpal, S.; Karlsson, M.; Thorn, H.; Stralfors, P. Cholesterol depletion disrupts caveolae and insulin receptor signaling for metabolic control via insulin receptor substrate-1, but not for mitogen-activated protein kinase control. J. Biol. Chem. 2001, 276, 9670-9678.
243. Yamamoto, M.; Toya, Y.; Schwencke, C.; Lisanti, M.P.; Myers, M.G., Jr.; Ishikawa, Y. Caveolin is an activator of insulin receptor signaling. J. Biol. Chem. 1998, 273, 26962-26968.
244. Matthews, L.C.; Taggart, M.J.; Westwood, M. Effect of cholesterol depletion on mitogenesis and survival: the role of caveolar and noncaveolar domains in insulin-like growth factor-mediated cellular function. Endocrinology 2005, 146, 5463-5473.
245. Storch, C.H.; Ehehalt, R.; Haefeli, W.E.; Weiss, J. Localization of the human breast cancer resistance protein (BCRP/ABCG2) in lipid rafts/caveolae and modulation of its activity by cholesterol in vitro. J. Pharmacol. Exp. Ther. 2007, 323, 257-264.
246. Awad, A.B.; Chinnam, M.; Fink, C.S.; Bradford, P.G. Beta-sitosterol activates Fas signaling in human breast cancer cells. Phytomedicine 2007, 14, 747-754.
247. Daniel, P.T.; Wieder, T.; Sturm, I.; Schulze-Osthoff, K. The kiss of death: Promises and failures of death receptors and ligands in cancer therapy. Leukemia 2001, 15, 1022-1032.
248. Ashkenazi, A.; Pai, R.C.; Fong, S.; Leung, S.; Lawrence, D.A.; Marsters, S.A.; Blackie, C.; Chang, L.; McMurtrey, A.E.; Hebert, A.; et al. Safety and antitumor activity of recombinant soluble Apo2 ligand. J. Clin. Invest. 1999, 104, 155-162.
249. Herbst, R.S.; Eckhardt, S.G.; Kurzrock, R.; Ebbinghaus, S.; O'Dwyer, P.J.; Gordon, M.S.; Novotny, W.; Goldwasser, M.A.; Tohnya, T.M.; Lum, B.L.; et al. Phase I dose-escalation study of recombinant human Apo2L/TRAIL, a dual proapoptotic receptor agonist, in patients with advanced cancer. J. Clin. Oncol. 2010, 28, 2839-2846.
250. Yin, S.; Xu, L.; Bandyopadhyay, S.; Sethi, S.; Reddy, K.B. Cisplatin and TRAIL enhance breast cancer stem cell death. Int. J. Oncol. 2011, 39, 891-898.
251. Muntane, J. Harnessing tumor necrosis factor receptors to enhance anti-tumor activities of drugs. Chem. Res. Toxicol. 2011, 24, 1610-1616.
252. Srivastava, R.K. TRAIL/Apo-2L: Mechanisms and clinical applications in cancer. Neoplasia 2001, 3, 535-546.
253. Pan, G.; O'Rourke, K.; Chinnaiyan, A.M.; Gentz, R.; Ebner, R.; Ni, J.; Dixit, V.M. The receptor for the cytotoxic ligand TRAIL. Science 1997, 276, 111-113.
254. Van Raam, B.J.; Salvesen, G.S. Proliferative versus apoptotic functions of caspase-8 Hetero or homo: The caspase-8 dimer controls cell fate. Biochim. Biophys. Acta 2011, 1824, 113-122.
255. Awad, A.B.; Roy, R.; Fink, C.S. Beta-sitosterol, a plant sterol, induces apoptosis and activates key caspases in MDA-MB-231 human breast cancer cells. Oncol. Rep. 2003, 10, 497-500.
256. Park, C.; Moon, D.O.; Ryu, C.H.; Choi, B.; Lee, W.; Kim, G.Y.; Choi, Y. Beta-sitosterol sensitizes MDA-MB-231 cells to TRAIL-induced apoptosis. Acta Pharmacol. Sin. 2008, 29, 341-348.
257. Awad, A.B.; Downie, A.; Fink, C.S.; Kim, U. Dietary phytosterol inhibits the growth and metastasis of MDA-MB-231 human breast cancer cells grown in SCID mice. Anticancer Res. 2000, 20, 821-824.
258. Ju, Y.H.; Clausen, L.M.; Allred, K.F.; Almada, A.L.; Helferich, W.G. Beta-sitosterol, beta-Sitosterol Glucoside, and a Mixture of beta-sitosterol and beta-sitosterol glucoside modulate the growth of estrogen-responsive breast cancer cells in vitro and in ovariectomized athymic mice. J. Nutr. 2004, 134, 1145-1151.
259. Danaei, G.; Vander Hoorn, S.; Lopez, A.D.; Murray, C.J.; Ezzati, M. Causes of cancer in the world: Comparative risk assessment of nine behavioural and environmental risk factors. Lancet 2005, 366, 1784-1793.