Abstract
We had shown Nw-hydroxy-l-arginine (NOHA) as a promising blood-based biomarker for estrogen-receptor-negative (ER−) breast cancer (BC) that differentiates ER− BC based on grade and molecular phenotype. In this in vitro study, we assessed the metabolic relevance for ER− BC-specific NOHA modulation and correlated them with NOHA regulatory responses. This study aids future NOHA clinical utility in ER− BC diagnosis and therapy management and would prove useful for potential drug discovery and development process.
Change history
17 November 2018
We found a unit error with our LC–MS lower limit of quantitation (LLOQ) measurement in the Amino Acids Journal
17 November 2018
We found a unit error with our LC���MS lower limit of quantitation (LLOQ) measurement in the Amino Acids Journal
References
Anders CK, Carey LA (2009) Biology, metastatic patterns, and treatment of patients with triple-negative breast cancer. Clin Breast Cancer 9(Suppl 2):S73–S81. https://doi.org/10.3816/CBC.2009.s.008
Anderson BO, Distelhorst SR (2008) Guidelines for International Breast Health and Cancer Control-Implementation. Introduction. Cancer 113(8 Suppl):2215–2216. https://doi.org/10.1002/cncr.23980
Anderson BO, Yip CH, Smith RA, Shyyan R, Sener SF, Eniu A, Carlson RW, Azavedo E, Harford J (2008) Guideline implementation for breast healthcare in low-income and middle-income countries: overview of the Breast Health Global Initiative Global Summit 2007. Cancer 113(8 Suppl):2221–2243. https://doi.org/10.1002/cncr.23844
Asobayire A, Barley R (2015) Women’s cultural perceptions and attitudes towards breast cancer: Northern Ghana. Health Promot Int 30(3):647–657. https://doi.org/10.1093/heapro/dat087
Bentzon N, During M, Rasmussen BB, Mouridsen H, Kroman N (2008) Prognostic effect of estrogen receptor status across age in primary breast cancer. Int J Cancer 122(5):1089–1094. https://doi.org/10.1002/ijc.22892
Berry DA, Cronin KA, Plevritis SK, Fryback DG, Clarke L, Zelen M, Mandelblatt JS, Yakovlev AY, Habbema JD, Feuer EJ, Cancer I, Surveillance Modeling Network C (2005) Effect of screening and adjuvant therapy on mortality from breast cancer. N Engl J Med 353(17):1784–1792. https://doi.org/10.1056/nejmoa050518
Boucher JL, Custot J, Vadon S, Delaforge M, Lepoivre M, Tenu JP, Yapo A, Mansuy D (1994) N omega-hydroxyl-l-arginine, an intermediate in the l-arginine to nitric oxide pathway, is a strong inhibitor of liver and macrophage arginase. Biochem Biophys Res Commun 203(3):1614–1621
Cancer Trends Progress Report-2017 update (2017). https://progressreport.cancer.gov/sites/default/files/archive/report2017.pdf
Carey LA, Perou CM, Livasy CA, Dressler LG, Cowan D, Conway K, Karaca G, Troester MA, Tse CK, Edmiston S, Deming SL, Geradts J, Cheang MC, Nielsen TO, Moorman PG, Earp HS, Millikan RC (2006) Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA 295(21):2492–2502. https://doi.org/10.1001/jama.295.21.2492
Chatziharalambous D, Lygirou V, Latosinska A, Stravodimos K, Vlahou A, Jankowski V, Zoidakis J (2016) Analytical performance of ELISA assays in urine: one more bottleneck towards biomarker validation and clinical implementation. PLoS One 11(2):e0149471. https://doi.org/10.1371/journal.pone.0149471
Chopra R (2001) The Indian scene. J Clin Oncol 19(18 Suppl):106S–111S
Daghigh F, Fukuto JM, Ash DE (1994) Inhibition of rat liver arginase by an intermediate in NO biosynthesis, NG-hydroxy-l-arginine: implications for the regulation of nitric oxide biosynthesis by arginase. Biochem Biophys Res Commun 202(1):174–180. https://doi.org/10.1006/bbrc.1994.1909
Dunnwald LK, Rossing MA, Li CI (2007) Hormone receptor status, tumor characteristics, and prognosis: a prospective cohort of breast cancer patients. Breast Cancer Res 9(1):R6. https://doi.org/10.1186/bcr1639
Farmer P, Frenk J, Knaul FM, Shulman LN, Alleyne G, Armstrong L, Atun R, Blayney D, Chen L, Feachem R, Gospodarowicz M, Gralow J, Gupta S, Langer A, Lob-Levyt J, Neal C, Mbewu A, Mired D, Piot P, Reddy KS, Sachs JD, Sarhan M, Seffrin JR (2010) Expansion of cancer care and control in countries of low and middle income: a call to action. Lancet 376(9747):1186–1193. https://doi.org/10.1016/S0140-6736(10)61152-X
Garlichs CD, Beyer J, Zhang H, Schmeisser A, Plotze K, Mugge A, Schellong S, Daniel WG (2000) Decreased plasma concentrations of l-hydroxy-arginine as a marker of reduced NO formation in patients with combined cardiovascular risk factors. J Lab Clin Med 135(5):419–425. https://doi.org/10.1067/mlc.2000.105975
Glynn SA, Boersma BJ, Dorsey TH, Yi M, Yfantis HG, Ridnour LA, Martin DN, Switzer CH, Hudson RS, Wink DA, Lee DH, Stephens RM, Ambs S (2010) Increased NOS2 predicts poor survival in estrogen receptor-negative breast cancer patients. J Clin Investig 120(11):3843–3854. https://doi.org/10.1172/JCI42059
Greenlee RT, Murray T, Bolden S, Wingo PA (2000) Cancer statistics, 2000. CA Cancer J Clin 50(1):7–33
Hecker M, Nematollahi H, Hey C, Busse R, Racke K (1995a) Inhibition of arginase by NG-hydroxy-l-arginine in alveolar macrophages: implications for the utilization of l-arginine for nitric oxide synthesis. FEBS Lett 359(2–3):251–254
Hecker M, Schott C, Bucher B, Busse R, Stoclet JC (1995b) Increase in serum NG-hydroxy-l-arginine in rats treated with bacterial lipopolysaccharide. Eur J Pharmacol 275(1):R1–R3
Heinecke JL, Ridnour LA, Cheng RY, Switzer CH, Lizardo MM, Khanna C, Glynn SA, Hussain SP, Young HA, Ambs S, Wink DA (2014) Tumor microenvironment-based feed-forward regulation of NOS2 in breast cancer progression. Proc Natl Acad Sci USA 111(17):6323–6328. https://doi.org/10.1073/pnas.1401799111
Jager K, Garreis F, Dunse M, Paulsen FP (2010) Cationic amino acid transporters and beta-defensins in dry eye syndrome. Dev Ophthalmol 45:12–15. https://doi.org/10.1159/000315015
Klatt P, Schmidt K, Uray G, Mayer B (1993) Multiple catalytic functions of brain nitric oxide synthase. Biochemical characterization, cofactor-requirement, and the role of N omega-hydroxy-l-arginine as an intermediate. J Biol Chem 268(20):14781–14787
Litzenburger BC, Brown PH (2014) Advances in preventive therapy for estrogen-receptor-negative breast cancer. Curr Breast Cancer Rep 6:96–109. https://doi.org/10.1007/s12609-014-0144-1
MacLeod CL, Finley KD, Kakuda DK (1994) y(+)-type cationic amino acid transport: expression and regulation of the mCAT genes. J Exp Biol 196:109–121
Mohan S, Wu CC, Shin S, Fung HL (2012) Continuous exposure to l-arginine induces oxidative stress and physiological tolerance in cultured human endothelial cells. Amino Acids 43(3):1179–1188. https://doi.org/10.1007/s00726-011-1173-y
Mohan S, Moua N, Harding L (2016) N w-Hydroxy-l-arginine as a novel ethnic specific indicator of estrogen-negative breast cancer. Amino Acids. https://doi.org/10.1007/s00726-016-2301-5
Mohan S, Greenstein I, Ng C, Frazier K, Nguyen G, Harding L, Barlow D (2017) Assessing N (w)-hydroxy-l-arginine applicability as a novel ethnic specific estrogen-negative breast cancer marker. Amino Acids. https://doi.org/10.1007/s00726-017-2523-1
Nystrom L, Andersson I, Bjurstam N, Frisell J, Nordenskjold B, Rutqvist LE (2002) Long-term effects of mammography screening: updated overview of the Swedish randomised trials. Lancet 359(9310):909–919. https://doi.org/10.1016/S0140-6736(02)08020-0
Onitilo AA, Engel JM, Greenlee RT, Mukesh BN (2009) Breast cancer subtypes based on ER/PR and Her2 expression: comparison of clinicopathologic features and survival. Clin Med Res 7(1–2):4–13. https://doi.org/10.3121/cmr.2009.825
Patel K, Strother RM, Ndiangui F, Chumba D, Jacobson W, Dodson C, Resnic MB, Strate RW, Smith JW (2016) Development of immunohistochemistry services for cancer care in western Kenya: implications for low- and middle-income countries. Afr J Lab Med 5(1):187. https://doi.org/10.4102/ajlm.v5i1.187
Pervin S, Singh R, Chaudhuri G (2008) Nitric oxide, N omega-hydroxy-l-arginine and breast cancer. Nitric Oxide 19(2):103–106. https://doi.org/10.1016/j.niox.2008.04.016
Simmons WW, Closs EI, Cunningham JM, Smith TW, Kelly RA (1996) Cytokines and insulin induce cationic amino acid transporter (CAT) expression in cardiac myocytes. Regulation of l-arginine transport and no production by CAT-1, CAT-2A, and CAT-2B. J Biol Chem 271(20):11694–11702
Stuehr DJ, Kwon NS, Nathan CF, Griffith OW, Feldman PL, Wiseman J (1991) N omega-hydroxy-l-arginine is an intermediate in the biosynthesis of nitric oxide from l-arginine. J Biol Chem 266(10):6259–6263
Vervoort MM, Draisma G, Fracheboud J, van de Poll-Franse LV, de Koning HJ (2004) Trends in the usage of adjuvant systemic therapy for breast cancer in the Netherlands and its effect on mortality. Br J Cancer 91(2):242–247. https://doi.org/10.1038/sj.bjc.6601969
Wanasen N, MacLeod CL, Ellies LG, Soong L (2007) l-Arginine and cationic amino acid transporter 2B regulate growth and survival of Leishmania amazonensis amastigotes in macrophages. Infect Immun 75(6):2802–2810. https://doi.org/10.1128/IAI.00026-07
Zotov V, Shyyan R, Program PBCA (2003) Introduction of breast cancer screening in Chernihiv Oblast in the Ukraine: report of a PATH Breast Cancer Assistance Program experience. Breast J 9(Suppl 2):S75–S80
Acknowledgements
The University of New England office of research and scholarship, and the college of Pharmacy provided funding support to this study.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
As the authors of this manuscript, we declare no conflict of interest; either financial or otherwise.
Research involving human participants and/or animals
No human participants or animal model were involved with this project, thus exempting this study from animal/human approval process.
Informed consent
No patient samples or bio-bank samples were used for this study, thus exempting informed consent requirement.
Additional information
Handling Editor: G. J. Peters.
Electronic supplementary material
Below is the link to the electronic supplementary material.
726_2018_2603_MOESM1_ESM.jpg
Supplemental Fig. 1. NOHA NOS2 and NO measurement of 3D spheroids cultured in medium containing 0.3 mM l-Lysine over 10 weeks. Each of the 6 distinct ER– BC cultured as 3D spheroids in medium containing 0.3 mM l-Lysine were monitored at the end of weeks 2, 6, and 10 for (A) NOHA in culture medium, (B) cellular NOHA, (C) cellular NOS2 expression, and (D) cellular NO production, as total nitrite, at n = 6. (JPEG 245 kb)
726_2018_2603_MOESM2_ESM.jpg
Supplemental Fig. 2. Arginase and CAT measurement of 3D spheroids cultured in medium containing 0.3 mM l-Lysine over 10 weeks. Each of the 6 distinct ER– BC cultured as 3D spheroids in medium containing 0.3 mM l-Lysine were monitored at the end of weeks 2, 6, and 10 for (A) cellular Arginase expression, (B) cellular Arginase activity, (C) CAT 1 expression, and (D) CAT 2 expression, at n = 6. (JPEG 265 kb)
Rights and permissions
About this article
Cite this article
Mohan, S., Patel, S., Greenstein, I. et al. Metabolic relevance for N-hydroxy l-arginine reduction in estrogen-negative breast cancer cells. Amino Acids 50, 1629–1636 (2018). https://doi.org/10.1007/s00726-018-2603-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00726-018-2603-x