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01-01-2013 | Brief Report

High stearoyl-CoA desaturase 1 expression is associated with shorter survival in breast cancer patients

Authors: Ashley M. Holder, Ana M. Gonzalez-Angulo, Huiqin Chen, Argun Akcakanat, Kim-Anh Do, W. Fraser Symmans, Lajos Pusztai, Gabriel N. Hortobagyi, Gordon B. Mills, Funda Meric-Bernstam

Published in: Breast Cancer Research and Treatment | Issue 1/2013

Abstract

Stearoyl-CoA desaturase 1 (SCD1) is an essential regulator of fatty acid synthesis. We have previously shown that overexpression of SCD1 increases the growth of breast cancer cell lines. The purpose of this study was to determine the relationship between SCD1 expression level and clinical-pathologic characteristics and survival of patients with breast cancer. Fine-needle aspirates were collected from the primary tumors of 250 patients with stage I–III breast cancer. Demographic and clinical characteristics including patient age, ethnicity, and menopausal status and tumor clinical stage, grade, and subtype were reviewed. SCD1 expression was analyzed using reverse-phase protein arrays. Samples were divided into high or low SCD1 expression levels based on a cut-off determined from martingale residual plots and regression tree analysis. SCD1 levels were significantly higher in tumors from patients >50-years old compared to patients ≤50-years old and were lower in triple-negative (estrogen/progesterone receptor-negative and human epidermal growth factor receptor-2-negative) breast cancers than other tumor subtypes. After adjusting for patient age, tumor subtype, tumor grade, and clinical stage, we found that patients with primary breast cancers expressing high SCD1 levels had significantly shorter relapse-free survival (RFS) (P = 0.0140) and overall survival (OS) (P = 0.039) in multivariable analysis. We conclude that SCD1 expression varies by breast cancer subtype and that high levels of SCD1 expression are associated with significantly shorter RFS and OS in multivariable analysis. Future studies are needed to define the role of SCD1 in the malignant phenotype of breast cancer and to evaluate the potential for SCD1 as a therapeutic target.

Ntambi JM (1999) Regulation of stearoyl-CoA desaturase by polyunsaturated fatty acids and cholesterol. J Lipid Res 40(9):1549–1558PubMed

Igal RA (2010) Stearoyl-CoA desaturase-1: a novel key player in the mechanisms of cell proliferation, programmed cell death and transformation to cancer. Carcinogenesis 31(9):1509–1515. doi:10.1093/carcin/bgq131 PubMedCrossRef

Enoch HG, Catala A, Strittmatter P (1976) Mechanism of rat liver microsomal stearyl-CoA desaturase. Studies of the substrate specificity, enzyme-substrate interactions, and the function of lipid. J Biol Chem 251(16):5095–5103PubMed

Zhang L, Ge L, Parimoo S, Stenn K, Prouty SM (1999) Human stearoyl-CoA desaturase: alternative transcripts generated from a single gene by usage of tandem polyadenylation sites. Biochem J 340(Pt 1):255–264PubMedCrossRef

Luyimbazi D, Akcakanat A, McAuliffe PF, Zhang L, Singh G, Gonzalez-Angulo AM, Chen H, Do KA, Zheng Y, Hung MC, Mills GB, Meric-Bernstam F (2010) Rapamycin regulates stearoyl CoA desaturase 1 expression in breast cancer. Mol Cancer Ther 9(10):2770–2784. doi:10.1158/1535-7163.MCT-09-0980 PubMedCrossRef

Peterson TR, Sengupta SS, Harris TE, Carmack AE, Kang SA, Balderas E, Guertin DA, Madden KL, Carpenter AE, Finck BN, Sabatini DM (2011) mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. Cell 146(3):408–420. doi:10.1016/j.cell.2011.06.034 PubMedCrossRef

Duvel K, Yecies JL, Menon S, Raman P, Lipovsky AI, Souza AL, Triantafellow E, Ma Q, Gorski R, Cleaver S, Vander Heiden MG, MacKeigan JP, Finan PM, Clish CB, Murphy LO, Manning BD (2010) Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol Cell 39(2):171–183. doi:10.1016/j.molcel.2010.06.022 PubMedCrossRef

Cao Q, Mak KM, Lieber CS (2006) Leptin enhances alpha1(I) collagen gene expression in LX-2 human hepatic stellate cells through JAK-mediated H2O2-dependent MAPK pathways. J Cell Biochem 97(1):188–197. doi:10.1002/jcb.20622 PubMedCrossRef

Mauvoisin D, Prevost M, Ducheix S, Arnaud MP, Mounier C (2010) Key role of the ERK1/2 MAPK pathway in the transcriptional regulation of the Stearoyl-CoA Desaturase (SCD1) gene expression in response to leptin. Mol Cell Endocrinol 319(1–2):116–128. doi:10.1016/j.mce.2010.01.027 PubMedCrossRef

10.

Tabor DE, Kim JB, Spiegelman BM, Edwards PA (1999) Identification of conserved cis-elements and transcription factors required for sterol-regulated transcription of stearoyl-CoA desaturase 1 and 2. J Biol Chem 274(29):20603–20610PubMedCrossRef

11.

Mauvoisin D, Rocque G, Arfa O, Radenne A, Boissier P, Mounier C (2007) Role of the PI3-kinase/mTor pathway in the regulation of the stearoyl CoA desaturase (SCD1) gene expression by insulin in liver. J Cell Commun Signal 1(2):113–125. doi:10.1007/s12079-007-0011-1 PubMedCrossRef

12.

Cheneval D, Christy RJ, Geiman D, Cornelius P, Lane MD (1991) Cell-free transcription directed by the 422 adipose P2 gene promoter: activation by the CCAAT/enhancer binding protein. Proc Natl Acad Sci U S A 88(19):8465–8469PubMedCrossRef

13.

Christy RJ, Yang VW, Ntambi JM, Geiman DE, Landschulz WH, Friedman AD, Nakabeppu Y, Kelly TJ, Lane MD (1989) Differentiation-induced gene expression in 3T3-L1 preadipocytes: CCAAT/enhancer binding protein interacts with and activates the promoters of two adipocyte-specific genes. Genes Dev 3(9):1323–1335PubMedCrossRef

14.

Singh MV, Ntambi JM (1998) Nuclear factor 1 is essential for the expression of stearoyl-CoA desaturase 1 gene during preadipocyte differentiation. Biochim Biophys Acta 1398(2):148–156PubMedCrossRef

15.

Ferre P, Foufelle F (2007) SREBP-1c transcription factor and lipid homeostasis: clinical perspective. Horm Res 68(2):72–82. doi:10.1159/000100426 PubMedCrossRef

16.

Bryzgalova G, Gao H, Ahren B, Zierath JR, Galuska D, Steiler TL, Dahlman-Wright K, Nilsson S, Gustafsson JA, Efendic S, Khan A (2006) Evidence that oestrogen receptor-alpha plays an important role in the regulation of glucose homeostasis in mice: insulin sensitivity in the liver. Diabetologia 49(3):588–597. doi:10.1007/s00125-005-0105-3 PubMedCrossRef

17.

Gao H, Bryzgalova G, Hedman E, Khan A, Efendic S, Gustafsson JA, Dahlman-Wright K (2006) Long-term administration of estradiol decreases expression of hepatic lipogenic genes and improves insulin sensitivity in ob/ob mice: a possible mechanism is through direct regulation of signal transducer and activator of transcription 3. Mol Endocrinol 20(6):1287–1299. doi:10.1210/me.2006-0012 PubMedCrossRef

18.

Bryzgalova G, Lundholm L, Portwood N, Gustafsson JA, Khan A, Efendic S, Dahlman-Wright K (2008) Mechanisms of antidiabetogenic and body weight-lowering effects of estrogen in high-fat diet-fed mice. Am J Physiol Endocrinol Metab 295(4):E904–E912. doi:10.1152/ajpendo.90248.2008 PubMedCrossRef

19.

Cohen B, Novick D, Rubinstein M (1996) Modulation of insulin activities by leptin. Science 274(5290):1185–1188PubMedCrossRef

20.

Elam MB, Yellaturu C, Howell GE, Deng X, Cowan GS, Kumar P, Park EA, Hiler ML, Wilcox HG, Hughes TA, Cook GA, Raghow R (2009) Dysregulation of sterol regulatory element binding protein-1c in livers of morbidly obese women is associated with altered suppressor of cytokine signaling-3 and signal transducer and activator of transcription-1 signaling. Metabolism 59(4):587–598. doi:10.1016/j.metabol.2009.09.001 PubMedCrossRef

21.

Scaglia N, Caviglia JM, Igal RA (2005) High stearoyl-CoA desaturase protein and activity levels in simian virus 40 transformed-human lung fibroblasts. Biochim Biophys Acta 1687(1–3):141–151. doi:10.1016/j.bbalip.2004.11.015 PubMed

22.

Scaglia N, Chisholm JW, Igal RA (2009) Inhibition of stearoylcoa desaturase-1 inactivates acetyl-CoA carboxylase and impairs proliferation in cancer cells: role of AMPK. PLoS ONE 4(8):e6812PubMedCrossRef

23.

Li J, Ding SF, Habib NA, Fermor BF, Wood CB, Gilmour RS (1994) Partial characterization of a cDNA for human stearoyl-CoA desaturase and changes in its mRNA expression in some normal and malignant tissues. Int J Cancer 57(3):348–352PubMedCrossRef

24.

Yahagi N, Shimano H, Hasegawa K, Ohashi K, Matsuzaka T, Najima Y, Sekiya M, Tomita S, Okazaki H, Tamura Y, Iizuka Y, Nagai R, Ishibashi S, Kadowaki T, Makuuchi M, Ohnishi S, Osuga J, Yamada N (2005) Co-ordinate activation of lipogenic enzymes in hepatocellular carcinoma. Eur J Cancer 41(9):1316–1322. doi:10.1016/j.ejca.2004.12.037 PubMedCrossRef

25.

Thai SF, Allen JW, DeAngelo AB, George MH, Fuscoe JC (2001) Detection of early gene expression changes by differential display in the livers of mice exposed to dichloroacetic acid. Carcinogenesis 22(8):1317–1322PubMedCrossRef

26.

Roongta UV, Pabalan JG, Wang X, Ryseck R-P, Fargnoli J, Henley BJ, Yang W-P, Zhu J, Madireddi MT, Lawrence RM, Wong TW, Rupnow BA (2011) Cancer cell dependence on unsaturated fatty acids implicates stearoyl-CoA desaturase as a target for cancer therapy. Mol Cancer Res 9(11):1551–1561. doi:10.1158/1541-7786.mcr-11-0126 PubMedCrossRef

27.

Scaglia N, Igal RA (2008) Inhibition of Stearoyl-CoA Desaturase 1 expression in human lung adenocarcinoma cells impairs tumorigenesis. Int J Oncol 33(4):839–850PubMed

28.

Morgan-Lappe SE, Tucker LA, Huang X, Zhang Q, Sarthy AV, Zakula D, Vernetti L, Schurdak M, Wang J, Fesik SW (2007) Identification of Ras-related nuclear protein, targeting protein for xenopus kinesin-like protein 2, and stearoyl-CoA desaturase 1 as promising cancer targets from an RNAi-based screen. Cancer Res 67(9):4390–4398. doi:10.1158/0008-5472.CAN-06-4132 PubMedCrossRef

29.

Fritz V, Benfodda Z, Rodier G, Henriquet C, Iborra F, Avancès C, Allory Y, de la Taille A, Culine S, Blancou H, Cristol JP, Michel F, Sardet C, Fajas L (2010) Abrogation of de novo lipogenesis by stearoyl-CoA desaturase 1 inhibition interferes with oncogenic signaling and blocks prostate cancer progression in mice. Mol Cancer Ther 9(6):1740–1754. doi:10.1158/1535-7163.mct-09-1064 PubMedCrossRef

30.

Hess D, Chisholm JW, Igal RA (2010) Inhibition of stearoylCoA desaturase activity blocks cell cycle progression and induces programmed cell death in lung cancer cells. PLoS ONE 5(6):e11394. doi:10.1371/journal.pone.0011394 PubMedCrossRef

31.

Pala V, Krogh V, Muti P, Chajes V, Riboli E, Micheli A, Saadatian M, Sieri S, Berrino F (2001) Erythrocyte membrane fatty acids and subsequent breast cancer: a prospective Italian study. J Natl Cancer Inst 93(14):1088–1095PubMedCrossRef

32.

Chajes V, Hulten K, Van Kappel AL, Winkvist A, Kaaks R, Hallmans G, Lenner P, Riboli E (1999) Fatty-acid composition in serum phospholipids and risk of breast cancer: an incident case–control study in Sweden. Int J Cancer 83(5):585–590. doi:10.1002/(SICI)1097-0215 PubMedCrossRef

33.

Chajes V, Thiebaut AC, Rotival M, Gauthier E, Maillard V, Boutron-Ruault MC, Joulin V, Lenoir GM, Clavel-Chapelon F (2008) Association between serum trans-monounsaturated fatty acids and breast cancer risk in the E3 N-EPIC Study. Am J Epidemiol 167(11):1312–1320. doi:10.1093/aje/kwn069 PubMedCrossRef

34.

Shannon J, King IB, Moshofsky R, Lampe JW, Gao DL, Ray RM, Thomas DB (2007) Erythrocyte fatty acids and breast cancer risk: a case–control study in Shanghai. China Am J Clin Nutr 85(4):1090–1097

35.

McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM (2006) REporting recommendations for tumor MARKer prognostic studies (REMARK). Breast Cancer Res Treat 100(2):229–235. doi:10.1007/s10549-006-9242-8 PubMedCrossRef

36.

Caudle AS, Gonzalez-Angulo AM, Hunt KK, Liu P, Pusztai L, Symmans WF, Kuerer HM, Mittendorf EA, Hortobagyi GN, Meric-Bernstam F (2010) Predictors of tumor progression during neoadjuvant chemotherapy in breast cancer. J Clin Oncol 28(11):1821–1828. doi:10.1200/JCO.2009.25.3286 PubMedCrossRef

37.

Gonzalez-Angulo AM, Hennessy BT, Meric-Bernstam F, Sahin A, Liu W, Ju Z, Carey MS, Myhre S, Speers C, Deng L, Broaddus R, Lluch A, Aparicio S, Brown P, Pusztai L, Symmans WF, Alsner J, Overgaard J, Borresen-Dale AL, Hortobagyi GN, Coombes KR, Mills GB (2011) Functional proteomics can define prognosis and predict pathologic complete response in patients with breast cancer. Clin Proteomics 8(1):11. doi:10.1186/1559-0275-8-11 PubMedCrossRef

38.

Meric-Bernstam F, Akcakanat A, Chen H, Do KA, Sangai T, Adkins F, Gonzalez-Angulo AM, Rashid A, Crosby K, Dong M, Phan AT, Wolff RA, Gupta S, Mills GB, Yao J (2012) PIK3CA/PTEN mutations and Akt activation as markers of sensitivity to allosteric mTOR inhibitors. Clin Cancer Res 18(6):1777–1789. doi:10.1158/1078-0432.CCR-11-2123 PubMedCrossRef

39.

Gewinner C, Wang ZC, Richardson A, Teruya-Feldstein J, Etemadmoghadam D, Bowtell D, Barretina J, Lin WM, Rameh L, Salmena L, Pandolfi PP, Cantley LC (2009) Evidence that inositol polyphosphate 4-phosphatase type II is a tumor suppressor that inhibits PI3 K signaling. Cancer Cell 16(2):115–125. doi:10.1016/j.ccr.2009.06.006 PubMedCrossRef

40.

Falvella FS, Pascale RM, Gariboldi M, Manenti G, De Miglio MR, Simile MM, Dragani TA, Feo F (2002) Stearoyl-CoA desaturase 1 (SCD1) gene overexpression is associated with genetic predisposition to hepatocarcinogenesis in mice and rats. Carcinogenesis 23(11):1933–1936PubMedCrossRef

41.

Bougnoux P, Chajes V, Lanson M, Hacene K, Body G, Couet C, Le Floch O (1992) Prognostic significance of tumor phosphatidylcholine stearic acid level in breast carcinoma. Breast Cancer Res Treat 20(3):185–194PubMedCrossRef

42.

Ntambi JM, Miyazaki M, Stoehr JP, Lan H, Kendziorski CM, Yandell BS, Song Y, Cohen P, Friedman JM, Attie AD (2002) Loss of stearoyl-CoA desaturase-1 function protects mice against adiposity. Proc Natl Acad Sci USA 99(17):11482–11486PubMedCrossRef

43.

Jiang G, Li Z, Liu F, Ellsworth K, Dallas-Yang Q, Wu M, Ronan J, Esau C, Murphy C, Szalkowski D, Bergeron R, Doebber T, Zhang BB (2005) Prevention of obesity in mice by antisense oligonucleotide inhibitors of stearoyl-CoA desaturase-1. J Clin Invest 115(4):1030–1038PubMed

44.

Dillon R, Greig MJ, Bhat BG (2008) Development of a novel LC/MS method to quantitate cellular stearoyl-CoA desaturase activity. Anal Chim Acta 627(1):99–104PubMedCrossRef

45.

Xin Z, Zhao H, Serby MD, Liu B, Liu M, Szczepankiewicz BG, Nelson LT, Smith HT, Suhar TS, Janis RS, Cao N, Camp HS, Collins CA, Sham HL, Surowy TK, Liu G (2008) Discovery of piperidine-aryl urea-based stearoyl-CoA desaturase 1 inhibitors. Bioorg Med Chem Lett 18(15):4298–4302PubMedCrossRef

46.

Soulard P, McLaughlin M, Stevens J, Connolly B, Coli R, Wang L, Moore J, Kuo MS, LaMarr WA, Ozbal CC, Bhat BG (2008) Development of a high-throughput screening assay for stearoyl-CoA desaturase using rat liver microsomes, deuterium labeled stearoyl-CoA and mass spectrometry. Anal Chim Acta 627(1):105–111PubMedCrossRef

Title: High stearoyl-CoA desaturase 1 expression is associated with shorter survival in breast cancer patients
Authors: Ashley M. Holder
Ana M. Gonzalez-Angulo
Huiqin Chen
Argun Akcakanat
Kim-Anh Do
W. Fraser Symmans
Lajos Pusztai
Gabriel N. Hortobagyi
Gordon B. Mills
Funda Meric-Bernstam
Publication date: 01-01-2013
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 1/2013
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-012-2354-4

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