Top

Published in:

01-08-2016 | Review

The Contribution of Cholesterol and Its Metabolites to the Pathophysiology of Breast Cancer

Authors: Amy E. Baek, Erik R. Nelson

Published in: Discover Oncology | Issue 4/2016

Abstract

As the most common cancer in women, one in eight will develop invasive breast cancer over their lifetime making it the second most common cause of cancer-related death among women. Of the many known risk factors for developing breast cancer, obesity stands out as prominent and modifiable. Interestingly, elevated cholesterol is highly associated with obesity and has emerged as an independent risk factor for breast cancer onset and recurrence. This indicates that cholesterol also contributes to the breast cancer pathogenicity of obesity. This review highlights our current understanding of the mechanisms by which cholesterol impacts breast cancer. Key preclinical studies have been highlighted, including the discussion of homeostatic control of cholesterol levels, signaling by cholesterol metabolites through the estrogen receptors, cholesterol formation of lipid rafts and subsequent signaling, and the potential roles of cholesterol in creating a pro-inflammatory tumor microenvironment. Future directions and avenues for therapeutic exploitation are also considered.

Ahern TP, Pedersen L, Tarp M, Cronin-Fenton DP, Garne JP, Silliman RA, Sorensen HT, Lash TL (2011) Statin prescriptions and breast cancer recurrence risk: a Danish nationwide prospective cohort study. J Natl Cancer Inst 103(19):1461–1468. doi:10.1093/jnci/djr291 PubMedPubMedCentralCrossRef

Alikhani N, Ferguson RD, Novosyadlyy R, Gallagher EJ, Scheinman EJ, Yakar S, LeRoith D (2013) Mammary tumor growth and pulmonary metastasis are enhanced in a hyperlipidemic mouse model. Oncogene 32(8):961–967. doi:10.1038/onc.2012.113 PubMedCrossRef

Allott EH, Howard LE, Cooperberg MR, Kane CJ, Aronson WJ, Terris MK, Amling CL, Freedland SJ (2014) Serum lipid profile and risk of prostate cancer recurrence: results from the SEARCH database. Cancer Epidemiol Biomarkers Prev 23(11):2349–2356. doi:10.1158/1055-9965.EPI-14-0458 PubMedPubMedCentralCrossRef

Amemiya-Kudo M, Shimano H, Hasty AH, Yahagi N, Yoshikawa T, Matsuzaka T, Okazaki H et al (2002) Transcriptional activities of nuclear SREBP-1a, −1c, and −2 to different target promoters of lipogenic and cholesterogenic genes. J Lipid Res 43(8):1220–1235PubMed

Anderson GL, Manson J, Wallace R, Lund B, Hall D, Davis S, Shumaker S, Wang CY, Stein E, Prentice RL (2003) Implementation of the Women’s Health Initiative study design. Ann Epidemiol 13(9 Suppl):S5–S17PubMedCrossRef

Bahl M, Ennis M, Tannock IF, Hux JE, Pritchard KI, Koo J, Goodwin PJ (2005) Serum lipids and outcome of early-stage breast cancer: results of a prospective cohort study. Breast Cancer Res Treat 94(2):135–144. doi:10.1007/s10549-005-6654-9 PubMedCrossRef

Beck P, Wysowski DK, Downey W, Butler-Jones D (2003) Statin use and the risk of breast cancer. J Clin Epidemiol 56(3):280–285PubMedCrossRef

Bennett MK, Seo YK, Datta S, Shin DJ, Osborne TF (2008) Selective binding of sterol regulatory element-binding protein isoforms and co-regulatory proteins to promoters for lipid metabolic genes in liver. J Biol Chem 283(23):15628–15637. doi:10.1074/jbc.M800391200 PubMedPubMedCentralCrossRef

Bensinger SJ, Bradley MN, Joseph SB, Zelcer N, Janssen EM, Hausner MA, Shih R et al (2008) LXR signaling couples sterol metabolism to proliferation in the acquired immune response. Cell 134(1):97–111. doi:10.1016/j.cell.2008.04.052 PubMedPubMedCentralCrossRef

10.

Berrino F, Villarini A, Traina A, Bonanni B, Panico S, Mano MP, Mercandino A et al (2014) Metabolic syndrome and breast cancer prognosis. Breast Cancer Res Treat 147(1):159–165. doi:10.1007/s10549-014-3076-6 PubMedCrossRef

11.

Beyea MM, Heslop CL, Sawyez CG, Edwards JY, Markle JG, Hegele RA, Huff MW (2007) Selective up-regulation of LXR-regulated genes ABCA1, ABCG1, and APOE in macrophages through increased endogenous synthesis of 24(S), 25-epoxycholesterol. J Biol Chem 282(8):5207–5216. doi:10.1074/jbc.M611063200 PubMedCrossRef

12.

Bianchini F, Kaaks R, Vainio H (2002) Overweight, obesity, and cancer risk. Lancet Oncol 3(9):565–574PubMedCrossRef

13.

Bjarnadottir O, Romero Q, Bendahl PO, Jirstrom K, Ryden L, Loman N, Uhlen M et al (2013) Targeting HMG-CoA reductase with statins in a window-of-opportunity breast cancer trial. Breast Cancer Res Treat 138(2):499–508. doi:10.1007/s10549-013-2473-6 PubMedCrossRef

14.

Blais L, Desgagne A, LeLorier J (2000) 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors and the risk of cancer: a nested case-control study. Arch Intern Med 160(15):2363–2368PubMedCrossRef

15.

Boudreau DM, Gardner JS, Malone KE, Heckbert SR, Blough DK, Daling JR (2004) The association between 3-hydroxy-3-methylglutaryl conenzyme A inhibitor use and breast carcinoma risk among postmenopausal women: a case-control study. Cancer 100(11):2308–2316. doi:10.1002/cncr.20271 PubMedCrossRef

16.

Brown MS, Dana SE, Goldstein JL (1973) Regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in human fibroblasts by lipoproteins. Proc Natl Acad Sci U S A 70(7):2162–2166PubMedPubMedCentralCrossRef

17.

Campbell MJ, Esserman LJ, Zhou Y, Shoemaker M, Lobo M, Borman E, Baehner F et al (2006) Breast cancer growth prevention by statins. Cancer Res 66(17):8707–8714. doi:10.1158/0008-5472.CAN-05-4061 PubMedCrossRef

18.

Cancer Genome Atlas Network (2012) Comprehensive molecular portraits of human breast tumours. Nature 490(7418):61–70. doi:10.1038/nature11412 CrossRef

19.

Capasso I, Esposito E, Pentimalli F, Crispo A, Montella M, Grimaldi M, De Marco M et al (2011) Metabolic syndrome affects breast cancer risk in postmenopausal women: National Cancer Institute of Naples experience. Cancer Biol Ther 10(12):1240–1243CrossRef

20.

Cauley JA, McTiernan A, Rodabough RJ, LaCroix A, Bauer DC, Margolis KL, Paskett ED et al (2006) Statin use and breast cancer: prospective results from the Women’s Health Initiative. J Natl Cancer Inst 98(10):700–707. doi:10.1093/jnci/djj188 PubMedCrossRef

21.

Cauley JA, Zmuda JM, Lui LY, Hillier TA, Ness RB, Stone KL, Cummings SR, Bauer DC (2003) Lipid-lowering drug use and breast cancer in older women: a prospective study. J Womens Health (Larchmt) 12(8):749–756. doi:10.1089/154099903322447710 CrossRef

22.

Centers fo Disease Control and Prevention (2010) Prevalence of abnormal lipid levels among youths—United States, 1999–2006. MMWR 59(2):29–33

23.

Chen Q, Zhang XH, Massague J (2011) Macrophage binding to receptor VCAM-1 transmits survival signals in breast cancer cells that invade the lungs. Cancer Cell 20(4):538–549. doi:10.1016/j.ccr.2011.08.025 PubMedPubMedCentralCrossRef

24.

Chittezhath M, Dhillon MK, Lim JY, Laoui D, Shalova IN, Teo YL, Chen J et al (2014) Molecular profiling reveals a tumor-promoting phenotype of monocytes and macrophages in human cancer progression. Immunity 41(5):815–829. doi:10.1016/j.immuni.2014.09.014 PubMedCrossRef

25.

Colditz GA, Rosner B (2000) Cumulative risk of breast cancer to age 70 years according to risk factor status: data from the Nurses’ Health Study. Am J Epidemiol 152(10):950–964PubMedCrossRef

26.

Collaborative Group on Hormonal Factors in Breast, Cancer (2012) Menarche, menopause, and breast cancer risk: individual participant meta-analysis, including 118 964 women with breast cancer from 117 epidemiological studies. Lancet Oncol 13(11):1141–1151. doi:10.1016/S1470-2045(12)70425-4 CrossRef

27.

Danilo C, Frank PG (2012) Cholesterol and breast cancer development. Curr Opin Pharmacol 12(6):677–682. doi:10.1016/j.coph.2012.07.009 PubMedCrossRef

28.

Das A, Brown MS, Anderson DD, Goldstein JL, Radhakrishnan A (2014) Three pools of plasma membrane cholesterol and their relation to cholesterol homeostasis. Elife (Cambridge) e02882. doi:10.7554/eLife.02882.

29.

Desai P, Chlebowski R, Cauley JA, Manson JE, Wu C, Martin LW, Jay A et al (2013) Prospective analysis of association between statin use and breast cancer risk in the women’s health initiative. Cancer Epidemiol Biomarkers Prev 22(10):1868–1876. doi:10.1158/1055-9965.EPI-13-0562 PubMedPubMedCentralCrossRef

30.

(1998) Design of the Women’s Health Initiative clinical trial and observational study. The Women’s Health Initiative Study Group. Control Clin Trials 19(1):61–109.

31.

Diaz-Montero CM, Salem ML, Nishimura MI, Garrett-Mayer E, Cole DJ, Montero AJ (2009) Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin-cyclophosphamide chemotherapy. Cancer Immunol Immunother 58(1):49–59. doi:10.1007/s00262-008-0523-4 PubMedCrossRef

32.

DuSell CD, Nelson ER, Wang X, Abdo J, Modder UI, Umetani M, Gesty-Palmer D, Javitt NB, Khosla S, McDonnell DP (2010) The endogenous selective estrogen receptor modulator 27-hydroxycholesterol is a negative regulator of bone homeostasis. Endocrinology 151(8):3675–3685. doi:10.1210/en.2010-0080 PubMedPubMedCentralCrossRef

33.

DuSell CD, Umetani M, Shaul PW, Mangelsdorf DJ, McDonnell DP (2008) 27-hydroxycholesterol is an endogenous selective estrogen receptor modulator. Mol Endocrinol 22(1):65–77. doi:10.1210/me.2007-0383 PubMedCrossRef

34.

Endogenous, Hormones, Group Breast Cancer Collaborative, Key TJ, Appleby PN, Reeves GK, Travis RC, Alberg AJ et al (2013) Sex hormones and risk of breast cancer in premenopausal women: a collaborative reanalysis of individual participant data from seven prospective studies. Lancet Oncol 14(10):1009–1019. doi:10.1016/S1470-2045(13)70301-2 CrossRef

35.

Ewertz M, Jensen MB, Gunnarsdottir KA, Hojris I, Jakobsen EH, Nielsen D, Stenbygaard LE, Tange UB, Cold S (2011) Effect of obesity on prognosis after early-stage breast cancer. J Clin Oncol 29(1):25–31. doi:10.1200/JCO.2010.29.7614 PubMedCrossRef

36.

Fessler MB (2015) Regulation of adaptive immunity in health and disease by cholesterol metabolism. Curr Allergy Asthma Rep 15(8):48. doi:10.1007/s11882-015-0548-7 PubMedCrossRef

37.

Flaveny CA, Griffett K, El-Gendy Bel D, Kazantzis M, Sengupta M, Amelio AL, Chatterjee A et al (2015) Broad anti-tumor activity of a small molecule that selectively targets the Warburg effect and lipogenesis. Cancer Cell 28(1):42–56. doi:10.1016/j.ccell.2015.05.007 PubMedCrossRef

38.

Friis S, Poulsen AH, Johnsen SP, McLaughlin JK, Fryzek JP, Dalton SO, Sorensen HT, Olsen JH (2005) Cancer risk among statin users: a population-based cohort study. Int J Cancer 114(4):643–647. doi:10.1002/ijc.20758 PubMedCrossRef

39.

Fu X, Menke JG, Chen Y, Zhou G, MacNaul KL, Wright SD, Sparrow CP, Lund EG (2001) 27-hydroxycholesterol is an endogenous ligand for liver X receptor in cholesterol-loaded cells. J Biol Chem 276(42):38378–38387. doi:10.1074/jbc.M105805200 PubMedCrossRef

40.

Gabrilovich DI, Nagaraj S (2009) Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 9(3):162–174. doi:10.1038/nri2506 PubMedPubMedCentralCrossRef

41.

Goldstein JL, Brown MS (1973) Familial hypercholesterolemia: identification of a defect in the regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity associated with overproduction of cholesterol. Proc Natl Acad Sci U S A 70(10):2804–2808PubMedPubMedCentralCrossRef

42.

Gostynski M, Gutzwiller F, Kuulasmaa K, Doring A, Ferrario M, Grafnetter D, Pajak A, Who Monica Project (2004) Analysis of the relationship between total cholesterol, age, body mass index among males and females in the WHO MONICA Project. Int J Obes Relat Metab Disord 28(8):1082–1090. doi:10.1038/sj.ijo.0802714 PubMedCrossRef

43.

Graaf MR, Beiderbeck AB, Egberts AC, Richel DJ, Guchelaar HJ (2004) The risk of cancer in users of statins. J Clin Oncol 22(12):2388–2394. doi:10.1200/JCO.2004.02.027 PubMedCrossRef

44.

Grivennikov SI, Greten FR, Karin M (2010) Immunity, inflammation, and cancer. Cell 140(6):883–899. doi:10.1016/j.cell.2010.01.025 PubMedPubMedCentralCrossRef

45.

Ha M, Sung J, Song YM (2009) Serum total cholesterol and the risk of breast cancer in postmenopausal Korean women. Cancer Causes Control 20(7):1055–1060. doi:10.1007/s10552-009-9301-7 PubMedCrossRef

46.

Haile LA, Gamrekelashvili J, Manns MP, Korangy F, Greten TF (2010) CD49d is a new marker for distinct myeloid-derived suppressor cell subpopulations in mice. J Immunol 185(1):203–210. doi:10.4049/jimmunol.0903573 PubMedCrossRef

47.

Hall JM, Lee MK, Newman B, Morrow JE, Anderson LA, Huey B, King MC (1990) Linkage of early-onset familial breast cancer to chromosome 17q21. Science 250(4988):1684–1689PubMedCrossRef

48.

Hong C, Tontonoz P (2014) Liver X receptors in lipid metabolism: opportunities for drug discovery. Nat Rev Drug Discov 13(6):433–444. doi:10.1038/nrd4280 PubMedCrossRef

49.

Hu J, La Vecchia C, de Groh M, Negri E, Morrison H, Mery L, Group Canadian Cancer Registries Epidemiology Research (2012) Dietary cholesterol intake and cancer. Ann Oncol 23(2):491–500. doi:10.1093/annonc/mdr155 PubMedCrossRef

50.

Hua X, Nohturfft A, Goldstein JL, Brown MS (1996) Sterol resistance in CHO cells traced to point mutation in SREBP cleavage-activating protein. Cell 87(3):415–426PubMedCrossRef

51.

Huang SH, Waldron JN, Milosevic M, Shen X, Ringash J, Su J, Tong L et al (2015) Prognostic value of pretreatment circulating neutrophils, monocytes, and lymphocytes in oropharyngeal cancer stratified by human papillomavirus status. Cancer 121(4):545–555. doi:10.1002/cncr.29100 PubMedCrossRef

52.

Jiralerspong S, Kim ES, Dong W, Feng L, Hortobagyi GN, Giordano SH (2013) Obesity, diabetes, and survival outcomes in a large cohort of early-stage breast cancer patients. Ann Oncol 24(10):2506–2514. doi:10.1093/annonc/mdt224 PubMedPubMedCentralCrossRef

53.

Jones LW, Alfano CM (2013) Exercise-oncology research: past, present, and future. Acta Oncol 52(2):195–215. doi:10.3109/0284186X.2012.742564 PubMedCrossRef

54.

Karuna R, Holleboom AG, Motazacker MM, Kuivenhoven JA, Frikke-Schmidt R, Tybjaerg-Hansen A, Georgopoulos S et al (2011) Plasma levels of 27-hydroxycholesterol in humans and mice with monogenic disturbances of high density lipoprotein metabolism. Atherosclerosis 214(2):448–455. doi:10.1016/j.atherosclerosis.2010.10.042 PubMedCrossRef

55.

Kaye JA, Jick H (2004) Statin use and cancer risk in the General Practice Research Database. Br J Cancer 90(3):635–637. doi:10.1038/sj.bjc.6601566 PubMedPubMedCentralCrossRef

56.

Kitahara CM, Berrington de Gonzalez A, Freedman ND, Huxley R, Mok Y, Jee SH, Samet JM (2011) Total cholesterol and cancer risk in a large prospective study in Korea. J Clin Oncol 29(12):1592–1598. doi:10.1200/JCO.2010.31.5200 PubMedPubMedCentralCrossRef

57.

Kwan ML, Habel LA, Flick ED, Quesenberry CP, Caan B (2008) Post-diagnosis statin use and breast cancer recurrence in a prospective cohort study of early stage breast cancer survivors. Breast Cancer Res Treat 109(3):573–579. doi:10.1007/s10549-007-9683-8 PubMedCrossRef

58.

Laffitte BA, Repa JJ, Joseph SB, Wilpitz DC, Kast HR, Mangelsdorf DJ, Tontonoz P (2001) LXRs control lipid-inducible expression of the apolipoprotein E gene in macrophages and adipocytes. Proc Natl Acad Sci U S A 98(2):507–512. doi:10.1073/pnas.021488798 PubMedPubMedCentralCrossRef

59.

Lappano R, Recchia AG, De Francesco EM, Angelone T, Cerra MC, Picard D, Maggiolini M (2011) The cholesterol metabolite 25-hydroxycholesterol activates estrogen receptor alpha-mediated signaling in cancer cells and in cardiomyocytes. PLoS One 6(1):e16631. doi:10.1371/journal.pone.0016631 PubMedPubMedCentralCrossRef

60.

Law JH, Habibi G, Hu K, Masoudi H, Wang MY, Stratford AL, Park E et al (2008) Phosphorylated insulin-like growth factor-i/insulin receptor is present in all breast cancer subtypes and is related to poor survival. Cancer Res 68(24):10238–10246. doi:10.1158/0008-5472.CAN-08-2755 PubMedCrossRef

61.

Lee JH, Gong H, Khadem S, Lu Y, Gao X, Li S, Zhang J, Xie W (2008) Androgen deprivation by activating the liver X receptor. Endocrinology 149(8):3778–3788. doi:10.1210/en.2007-1605 PubMedCrossRef

62.

Liu J, Xu A, Lam KS, Wong NS, Chen J, Shepherd PR, Wang Y (2013) Cholesterol-induced mammary tumorigenesis is enhanced by adiponectin deficiency: role of LDL receptor upregulation. Oncotarget 4(10):1804–1818PubMedPubMedCentralCrossRef

63.

Llaverias G, Danilo C, Mercier I, Daumer K, Capozza F, Williams TM, Sotgia F, Lisanti MP, Frank PG (2011) Role of cholesterol in the development and progression of breast cancer. Am J Pathol 178(1):402–412. doi:10.1016/j.ajpath.2010.11.005 PubMedPubMedCentralCrossRef

64.

Lo Sasso G, Murzilli S, Salvatore L, D’Errico I, Petruzzelli M, Conca P, Jiang ZY, Calabresi L, Parini P, Moschetta A (2010) Intestinal specific LXR activation stimulates reverse cholesterol transport and protects from atherosclerosis. Cell Metab 12(2):187–193. doi:10.1016/j.cmet.2010.07.002 PubMedCrossRef

65.

Lord SJ, Bernstein L, Johnson KA, Malone KE, McDonald JA, Marchbanks PA, Simon MS et al (2008) Breast cancer risk and hormone receptor status in older women by parity, age of first birth, and breastfeeding: a case-control study. Cancer Epidemiol Biomarkers Prev 17(7):1723–1730. doi:10.1158/1055-9965.EPI-07-2824 PubMedPubMedCentralCrossRef

66.

Luo Y, Zhou H, Krueger J, Kaplan C, Lee SH, Dolman C, Markowitz D et al (2006) Targeting tumor-associated macrophages as a novel strategy against breast cancer. J Clin Invest 116(8):2132–2141. doi:10.1172/JCI27648 PubMedPubMedCentralCrossRef

67.

Mafuvadze B, Liang Y, Hyder SM (2014) Cholesterol synthesis inhibitor RO 48-8071 suppresses transcriptional activity of human estrogen and androgen receptor. Oncol Rep 32(4):1727–1733. doi:10.3892/or.2014.3332 PubMed

68.

Martinez-Outschoorn UE, Sotgia F, Lisanti MP (2015) Caveolae and signalling in cancer. Nat Rev Cancer 15(4):225–237. doi:10.1038/nrc3915 PubMedCrossRef

69.

McPherson K, Steel CM, Dixon JM (2000) ABC of breast diseases. Breast cancer—epidemiology, risk factors, and genetics. BMJ 321(7261):624–628PubMedPubMedCentralCrossRef

70.

Michailidou K, Hall P, Gonzalez-Neira A, Ghoussaini M, Dennis J, Milne RL, Schmidt MK et al (2013) Large-scale genotyping identifies 41 new loci associated with breast cancer risk. Nat Genet 45(4):353–361. doi:10.1038/ng.2563, 361e351-352PubMedPubMedCentralCrossRef

71.

Michels KB, Solomon CG, Hu FB, Rosner BA, Hankinson SE, Colditz GA, Manson JE, Study Nurses’ Health (2003) Type 2 diabetes and subsequent incidence of breast cancer in the Nurses’ Health Study. Diabetes Care 26(6):1752–1758PubMedCrossRef

72.

Mundal L, Sarancic M, Ose L, Iversen PO, Borgan JK, Veierod MB, Leren TP, Retterstol K (2014) Mortality among patients with familial hypercholesterolemia: a registry-based study in Norway, 1992–2010. J Am Heart Assoc 3(6):e001236. doi:10.1161/JAHA.114.001236 PubMedPubMedCentralCrossRef

73.

Must A, Spadano J, Coakley EH, Field AE, Colditz G, Dietz WH (1999) The disease burden associated with overweight and obesity. JAMA 282(16):1523–1529PubMedCrossRef

74.

Nelson ER, Chang CY, McDonnell DP (2014) Cholesterol and breast cancer pathophysiology. Trends Endocrinol Metab 25(12):649–655. doi:10.1016/j.tem.2014.10.001 PubMedPubMedCentralCrossRef

75.

Nelson ER, DuSell CD, Wang X, Howe MK, Evans G, Michalek RD, Umetani M et al (2011) The oxysterol, 27-hydroxycholesterol, links cholesterol metabolism to bone homeostasis through its actions on the estrogen and liver X receptors. Endocrinology 152(12):4691–4705. doi:10.1210/en.2011-1298 PubMedPubMedCentralCrossRef

76.

Nelson ER, Wardell SE, Jasper JS, Park S, Suchindran S, Howe MK, Carver NJ et al (2013) 27-Hydroxycholesterol links hypercholesterolemia and breast cancer pathophysiology. Science 342(6162):1094–1098. doi:10.1126/science.1241908 PubMedPubMedCentralCrossRef

77.

Neuhouser ML, Aragaki AK, Prentice RL, Manson JE, Chlebowski R, Carty CL, Ochs-Balcom HM (2015) Overweight, obesity, and postmenopausal invasive breast cancer risk: a secondary analysis of the Women’s Health Initiative randomized clinical trials. JAMA Oncol. doi:10.1001/jamaoncol.2015.1546 PubMedCentral

78.

Neuhouser ML, Aragaki AK, Prentice RL, Manson JE, Chlebowski R, Carty CL, Ochs-Balcom HM et al (2015) Overweight, obesity, and postmenopausal invasive breast cancer risk: a secondary analysis of the Women’s Health Initiative randomized clinical trials. JAMA Onco 1(5):611–621. doi:10.1001/jamaoncol.2015.1546 CrossRef

79.

Nguyen-Vu T, Vedin LL, Liu K, Jonsson P, Lin JZ, Candelaria NR, Candelaria LP et al (2013) Liver X receptor ligands disrupt breast cancer cell proliferation through an E2F-mediated mechanism. Breast Cancer Res 15(3):R51. doi:10.1186/bcr3443 PubMedPubMedCentralCrossRef

80.

Nguyen VT, Barozzi I, Faronato M, Lombardo Y, Steel JH, Patel N, Darbre P et al (2015) Differential epigenetic reprogramming in response to specific endocrine therapies promotes cholesterol biosynthesis and cellular invasion. Nat Commun 6:10044. doi:10.1038/ncomms10044 PubMedPubMedCentralCrossRef

81.

Nielsen SF, Nordestgaard BG, Bojesen SE (2012) Statin use and reduced cancer-related mortality. N Engl J Med 367(19):1792–1802. doi:10.1056/NEJMoa1201735 PubMedCrossRef

82.

Ogden CL, Carroll MD, Kit BK, Flegal KM (2014) Prevalence of childhood and adult obesity in the United States, 2011–2012. JAMA 311(8):806–814. doi:10.1001/jama.2014.732 PubMedPubMedCentralCrossRef

83.

Ou J, Tu H, Shan B, Luk A, DeBose-Boyd RA, Bashmakov Y, Goldstein JL, Brown MS (2001) Unsaturated fatty acids inhibit transcription of the sterol regulatory element-binding protein-1c (SREBP-1c) gene by antagonizing ligand-dependent activation of the LXR. Proc Natl Acad Sci U S A 98(11):6027–6032. doi:10.1073/pnas.111138698 PubMedPubMedCentralCrossRef

84.

Pasanisi P, Berrino F, De Petris M, Venturelli E, Mastroianni A, Panico S (2006) Metabolic syndrome as a prognostic factor for breast cancer recurrences. Int J Cancer 119(1):236–238. doi:10.1002/ijc.21812 PubMedCrossRef

85.

Pelton K, Coticchia CM, Curatolo AS, Schaffner CP, Zurakowski D, Solomon KR, Moses MA (2014) Hypercholesterolemia induces angiogenesis and accelerates growth of breast tumors in vivo. Am J Pathol 184(7):2099–2110. doi:10.1016/j.ajpath.2014.03.006 PubMedPubMedCentralCrossRef

86.

Pencheva N, Buss CG, Posada J, Merghoub T, Tavazoie SF (2014) Broad-spectrum therapeutic suppression of metastatic melanoma through nuclear hormone receptor activation. Cell 156(5):986–1001. doi:10.1016/j.cell.2014.01.038 PubMedCrossRef

87.

Petracci E, Decarli A, Schairer C, Pfeiffer RM, Pee D, Masala G, Palli D, Gail MH (2011) Risk factor modification and projections of absolute breast cancer risk. J Natl Cancer Inst 103(13):1037–1048. doi:10.1093/jnci/djr172 PubMedPubMedCentralCrossRef

88.

Pierobon M, Frankenfeld CL (2013) Obesity as a risk factor for triple-negative breast cancers: a systematic review and meta-analysis. Breast Cancer Res Treat 137(1):307–314. doi:10.1007/s10549-012-2339-3 PubMedCrossRef

89.

Pommier AJ, Alves G, Viennois E, Bernard S, Communal Y, Sion B, Marceau G et al (2010) Liver X Receptor activation downregulates AKT survival signaling in lipid rafts and induces apoptosis of prostate cancer cells. Oncogene 29(18):2712–2723. doi:10.1038/onc.2010.30 PubMedCrossRef

90.

Qian BZ, Pollard JW (2010) Macrophage diversity enhances tumor progression and metastasis. Cell 141(1):39–51. doi:10.1016/j.cell.2010.03.014 PubMedCrossRef

91.

Raccosta L, Fontana R, Maggioni D, Lanterna C, Villablanca EJ, Paniccia A, Musumeci A et al (2013) The oxysterol–CXCR2 axis plays a key role in the recruitment of tumor-promoting neutrophils. J Exp Med 210(9):1711–1728. doi:10.1084/jem.20130440 PubMedPubMedCentralCrossRef

92.

Renehan AG, Roberts DL, Dive C (2008) Obesity and cancer: pathophysiological and biological mechanisms. Arch Physiol Biochem 114(1):71–83. doi:10.1080/13813450801954303 PubMedCrossRef

93.

Ries CH, Cannarile MA, Hoves S, Benz J, Wartha K, Runza V, Rey-Giraud F et al (2014) Targeting tumor-associated macrophages with anti-CSF-1R antibody reveals a strategy for cancer therapy. Cancer Cell 25(6):846–859. doi:10.1016/j.ccr.2014.05.016 PubMedCrossRef

94.

Ronco AL, De Stefani E, Stoll M (2010) Hormonal and metabolic modulation through nutrition: towards a primary prevention of breast cancer. Breast 19(5):322–332. doi:10.1016/j.breast.2010.05.005 PubMedCrossRef

95.

Sag D, Cekic C, Wu R, Linden J, Hedrick CC (2015) The cholesterol transporter ABCG1 links cholesterol homeostasis and tumour immunity. Nat Commun 6:6354. doi:10.1038/ncomms7354 PubMedPubMedCentralCrossRef

96.

Schultz JR, Tu H, Luk A, Repa JJ, Medina JC, Li L, Schwendner S et al (2000) Role of LXRs in control of lipogenesis. Genes Dev 14(22):2831–2838PubMedPubMedCentralCrossRef

97.

Shah R, Rosso K, Nathanson SD (2014) Pathogenesis, prevention, diagnosis and treatment of breast cancer. World J Clin Oncol 5(3):283–298. doi:10.5306/wjco.v5.i3.283 PubMedPubMedCentralCrossRef

98.

Shen M, Hu P, Donskov F, Wang G, Liu Q, Du J (2014) Tumor-associated neutrophils as a new prognostic factor in cancer: a systematic review and meta-analysis. PLoS One 9(6):e98259. doi:10.1371/journal.pone.0098259 PubMedPubMedCentralCrossRef

99.

Siegel RL, Miller KD, Jemal A (2015) Cancer statistics, 2015. CA Cancer J Clin 65(1):5–29. doi:10.3322/caac.21254 PubMedCrossRef

100.

Singletary SE (2003) Rating the risk factors for breast cancer. Ann Surg 237(4):474–482. doi:10.1097/01.SLA.0000059969.64262.87 PubMedPubMedCentral

101.

Solito S, Falisi E, Diaz-Montero CM, Doni A, Pinton L, Rosato A, Francescato S et al (2011) A human promyelocytic-like population is responsible for the immune suppression mediated by myeloid-derived suppressor cells. Blood 118(8):2254–2265. doi:10.1182/blood-2010-12-325753 PubMedPubMedCentralCrossRef

102.

Spann NJ, Glass CK (2013) Sterols and oxysterols in immune cell function. Nat Immunol 14(9):893–900. doi:10.1038/ni.2681 PubMedCrossRef

103.

Stewart CR, Stuart LM, Wilkinson K, van Gils JM, Deng J, Halle A, Rayner KJ et al (2010) CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nat Immunol 11(2):155–161. doi:10.1038/ni.1836 PubMedCrossRef

104.

Strachan DC, Ruffell B, Oei Y, Bissell MJ, Coussens LM, Pryer N, Daniel D (2013) CSF1R inhibition delays cervical and mammary tumor growth in murine models by attenuating the turnover of tumor-associated macrophages and enhancing infiltration by CD8 T cells. Oncoimmunology 2(12):e26968. doi:10.4161/onci.26968 PubMedPubMedCentralCrossRef

105.

Sullivan PM, Mezdour H, Aratani Y, Knouff C, Najib J, Reddick RL, Quarfordt SH, Maeda N (1997) Targeted replacement of the mouse apolipoprotein E gene with the common human APOE3 allele enhances diet-induced hypercholesterolemia and atherosclerosis. J Biol Chem 272(29):17972–17980PubMedCrossRef

106.

Thelen KM, Lutjohann D, Vesalainen R, Janatuinen T, Knuuti J, von Bergmann K, Lehtimaki T, Laaksonen R (2006) Effect of pravastatin on plasma sterols and oxysterols in men. Eur J Clin Pharmacol 62(1):9–14. doi:10.1007/s00228-005-0068-9 PubMedCrossRef

107.

Umetani M, Domoto H, Gormley AK, Yuhanna IS, Cummins CL, Javitt NB, Korach KS, Shaul PW, Mangelsdorf DJ (2007) 27-Hydroxycholesterol is an endogenous SERM that inhibits the cardiovascular effects of estrogen. Nat Med 13(10):1185–1192. doi:10.1038/nm1641 PubMedCrossRef

108.

Umetani M, Ghosh P, Ishikawa T, Umetani J, Ahmed M, Mineo C, Shaul PW (2014) The cholesterol metabolite 27-hydroxycholesterol promotes atherosclerosis via proinflammatory processes mediated by estrogen receptor alpha. Cell Metab 20(1):172–182. doi:10.1016/j.cmet.2014.05.013 PubMedPubMedCentralCrossRef

109.

Undela K, Srikanth V, Bansal D (2012) Statin use and risk of breast cancer: a meta-analysis of observational studies. Breast Cancer Res Treat 135(1):261–269. doi:10.1007/s10549-012-2154-x PubMedCrossRef

110.

Vedin LL, Lewandowski SA, Parini P, Gustafsson JA, Steffensen KR (2009) The oxysterol receptor LXR inhibits proliferation of human breast cancer cells. Carcinogenesis 30(4):575–579. doi:10.1093/carcin/bgp029 PubMedCrossRef

111.

Villablanca EJ, Raccosta L, Zhou D, Fontana R, Maggioni D, Negro A, Sanvito F et al (2010) Tumor-mediated liver X receptor-alpha activation inhibits CC chemokine receptor-7 expression on dendritic cells and dampens antitumor responses. Nat Med 16(1):98–105. doi:10.1038/nm.2074 PubMedCrossRef

112.

Wang X, Simpson ER, Brown KA (2015) Aromatase overexpression in dysfunctional adipose tissue links obesity to postmenopausal breast cancer. J Steroid Biochem Mol Biol 153:35–44. doi:10.1016/j.jsbmb.2015.07.008 PubMedCrossRef

113.

Waxler SH, Tabar P, Melcher LR (1953) Obesity and the time of appearance of spontaneous mammary carcinoma in C3H mice. Cancer Res 13(3):276–278PubMed

114.

White CP (1909) On the occurrence of crystals in tumours. J Pathol Bacteriol 13(1):3–10. doi:10.1002/path.1700130103 CrossRef

115.

Wu Q, Ishikawa T, Sirianni R, Tang H, McDonald JG, Yuhanna IS, Thompson B et al (2013) 27-Hydroxycholesterol promotes cell-autonomous, ER-positive breast cancer growth. Cell Rep 5(3):637–645. doi:10.1016/j.celrep.2013.10.006 PubMedPubMedCentralCrossRef

116.

Xuan QJ, Wang JX, Nanding A, Wang ZP, Liu H, Lian X, Zhang QY (2014) Tumor-associated macrophages are correlated with tamoxifen resistance in the postmenopausal breast cancer patients. Pathol Oncol Res 20(3):619–624. doi:10.1007/s12253-013-9740-z PubMedCrossRef

117.

Youn JI, Nagaraj S, Collazo M, Gabrilovich DI (2008) Subsets of myeloid-derived suppressor cells in tumor-bearing mice. J Immunol 181(8):5791–5802PubMedPubMedCentralCrossRef

118.

Zelcer N, Hong C, Boyadjian R, Tontonoz P (2009) LXR regulates cholesterol uptake through Idol-dependent ubiquitination of the LDL receptor. Science 325(5936):100–104. doi:10.1126/science.1168974 PubMedPubMedCentralCrossRef

119.

Zhang JR, Coleman T, Langmade SJ, Scherrer DE, Lane L, Lanier MH, Feng C et al (2008) Niemann-Pick C1 protects against atherosclerosis in mice via regulation of macrophage intracellular cholesterol trafficking. J Clin Invest 118(6):2281–2290. doi:10.1172/JCI32561 PubMedPubMedCentral

120.

Zhang L, Reue K, Fong LG, Young SG, Tontonoz P (2012) Feedback regulation of cholesterol uptake by the LXR–IDOL–LDLR axis. Arterioscler Thromb Vasc Biol 32(11):2541–2546. doi:10.1161/ATVBAHA.112.250571 PubMedPubMedCentralCrossRef

121.

Zhang QW, Liu L, Gong CY, Shi HS, Zeng YH, Wang XZ, Zhao YW, Wei YQ (2012) Prognostic significance of tumor-associated macrophages in solid tumor: a meta-analysis of the literature. PLoS One 7(12):e50946. doi:10.1371/journal.pone.0050946 PubMedPubMedCentralCrossRef

122.

Zhong S, Zhang X, Chen L, Ma T, Tang J, Zhao J (2015) Statin use and mortality in cancer patients: systematic review and meta-analysis of observational studies. Cancer Treat Rev 41(6):554–567. doi:10.1016/j.ctrv.2015.04.005 PubMedCrossRef

Title: The Contribution of Cholesterol and Its Metabolites to the Pathophysiology of Breast Cancer
Authors: Amy E. Baek
Erik R. Nelson
Publication date: 01-08-2016
Publisher: Springer US
Published in: Discover Oncology / Issue 4/2016
Print ISSN: 1868-8497
Electronic ISSN: 2730-6011
DOI: https://doi.org/10.1007/s12672-016-0262-5

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits

Illustration of figure on mountain summit/© Orapun / Stock.adobe.com, STEP AAG HeroTeaserCollection image/© Tarek / Generated with AI / Stock.adobe.com, ACC 2024 Pediatric and Congenital Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Pulmonary Vascular Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Valvular Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 HF and Cardiomyopathies: Year in Review/© 2024 American College of Cardiology, Woman out walking/© Seventyfour / stock.adobe.com (symbolic image with model), Woman checking smartwatch /© saltdium / stock.adobe.com (symbolic image with model), Cardiac catheterization/© Damian / stock.adobe.com

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 4/2016

The Effect of Implementing Gene Expression Classifier on Outcomes of Thyroid Nodules with Indeterminate Cytology

Bisphenol A (BPA) Exposure In Utero Leads to Immunoregulatory Cytokine Dysregulation in the Mouse Mammary Gland: A Potential Mechanism Programming Breast Cancer Risk

Loss of exogenous androgen dependence by prostate tumor cells is associated with elevated glucuronidation potential

Protein Biomarkers for Breast Cancer Risk Are Specifically Correlated with Local Steroid Hormones in Nipple Aspirate Fluid

Clinical Features, Treatments, and Outcomes of Patients with Thymic Carcinoids and Multiple Endocrine Neoplasia Type 1 Syndrome at MD Anderson Cancer Center

Patient-Derived Prostate Cancer: from Basic Science to the Clinic

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

Highlights from the ACC 2024 Congress

ACC 2024 Congress Coverage