Potential Biomarker of L-type Amino Acid Transporter 1 in Breast Cancer Progression
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L-type amino acid transporter 1 (LAT1) is essential for the transport of large neutral amino acids. However, its role in breast cancer growth remains largely unknown. The purpose of the study is to investigate whether LAT1 is a potential biomarker for the diagnosis and treatment of breast cancer.
LAT1 mRNA and protein levels in breast cancer cell lines and tissues were analyzed. In addition, the effects of targeting LAT1 for the inhibition of breast cancer cell tumorigenesis were assessed with soft agar assay. The imaging of xenograft with anti-1-amino-3-[18F]fluorocyclobutane-1-carboxylic acid (anti-[18F]FACBC) PET was assessed for its diagnostic biomarker potential.
Normal breast tissue or low malignant cell lines expressed low levels of LAT1 mRNA and protein, while highly malignant cancer cell lines and high-grade breast cancer tissue expressed high levels of LAT1. In addition, higher expression levels of LAT1 in breast cancer tissues were consistent with advanced-stage breast cancer. Furthermore, the blockade of LAT1 with its inhibitor, 2-amino-bicyclo[2.2.1]heptane-2-carboxylic acid (BCH), or the knockdown of LAT1 with siRNA, inhibited proliferation and tumorigenesis of breast cancer cells. A leucine analog, anti-[18F]FACBC, has been demonstrated to be an excellent PET tracer for the non-invasive imaging of malignant breast cancer using an orthotopic animal model.
The overexpression of LAT1 is required for the progression of breast cancer. LAT1 represents a potential biomarker for therapy and diagnosis of breast cancer. Anti-[18F]FACBC that correlates with LAT1 function is a potential PET tracer for malignant breast tumor imaging.
- Edwards BK, Ward E, Kohler BA, Eheman C, Zauber AG, Anderson RN, et al. Annual report to the nation on the status of cancer, 1975–2006, featuring colorectal cancer trends and impact of interventions (risk factors, screening, and treatment) to reduce future rates. Cancer. 2010;116:544–73. CrossRef
- Coughlin SS, Ekwueme DU. Breast cancer as a global health concern. Cancer Epidemiol. 2009;33:315–8. CrossRef
- Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74–108. CrossRef
- Anderson BO, Yip CH, Smith RA, Shyyan R, Sener SF, Eniu A, et al. Guideline implementation for breast healthcare in low-income and middle-income countries: overview of the Breast Health Global Initiative Global Summit 2007. Cancer. 2008;113:2221–43. CrossRef
- Porter P. “Westernizing” women's risks? Breast cancer in lower-income countries. N Engl J Med. 2008;358:213–6. CrossRef
- Kanai Y, Segawa H, Miyamoto K, Uchino H, Takeda E, Endou H. Expression cloning and characterization of a transporter for large neutral amino acids activated by the heavy chain of 4F2 antigen (CD98). J Biol Chem. 1998;273:23629–32. CrossRef
- Mastroberardino L, Spindler B, Pfeiffer R, Skelly PJ, Loffing J, Shoemaker CB, et al. Amino-acid transport by heterodimers of 4F2hc/CD98 and members of a permease family. Nature. 1998;395:288–91. CrossRef
- Yoon JH, Kim YB, Kim MS, Park JC, Kook JK, Jung HM, et al. Expression and functional characterization of the system L amino acid transporter in KB human oral epidermoid carcinoma cells. Cancer Lett. 2004;205:215–26. CrossRef
- Kobayashi H, Ishii Y, Takayama T. Expression of L-type amino acid transporter 1 (LAT1) in esophageal carcinoma. J Surg Oncol. 2005;90:233–8. CrossRef
- Lin J, Raoof DA, Thomas DG, Greenson JK, Giordano TJ, Robinson GS, et al. L-type amino acid transporter-1 overexpression and melphalan sensitivity in Barrett's adenocarcinoma. Neoplasia. 2004;6:74–84. CrossRef
- Nawashiro H, Otani N, Shinomiya N, Fukui S, Ooigawa H, Shima K, et al. L-type amino acid transporter 1 as a potential molecular target in human astrocytic tumors. Int J Cancer. 2006;119:484–92. CrossRef
- Nawashiro H, Otani N, Shinomiya N, Fukui S, Nomura N, Yano A, et al. The role of CD98 in astrocytic neoplasms. Hum Cell. 2002;15:25–31. CrossRef
- Nakanishi K, Matsuo H, Kanai Y, Endou H, Hiroi S, Tominaga S, et al. LAT1 expression in normal lung and in atypical adenomatous hyperplasia and adenocarcinoma of the lung. Virchows Arch. 2006;448:142–50. CrossRef
- Yoon JH, Kim IJ, Kim H, Kim HJ, Jeong MJ, Ahn SG, et al. Amino acid transport system L is differently expressed in human normal oral keratinocytes and human oral cancer cells. Cancer Lett. 2005;222:237–45. CrossRef
- Kim SG, Kim HH, Kim HK, Kim CH, Chun HS, Kanai Y, et al. Differential expression and functional characterization of system L amino acid transporters in human normal osteoblast cells and osteogenic sarcoma cells. Anticancer Res. 2006;26:1989–96.
- Christensen HN. Role of amino acid transport and countertransport in nutrition and metabolism. Physiol Rev. 1990;70:43–77.
- Shennan DB, Thomson J, Barber MC, Travers MT. Functional and molecular characteristics of system L in human breast cancer cells. Biochim Biophys Acta. 2003;1611:81–90. CrossRef
- Travers MT, Gow IF, Barber MC, Thomson J, Shennan DB. Indoleamine 2, 3-dioxygenase activity and L-tryptophan transport in human breast cancer cells. Biochim Biophys Acta. 2004;1661:106–12. CrossRef
- Shennan DB, Thomson J, Gow IF, Travers MT, Barber MC. L-leucine transport in human breast cancer cells (MCF-7 and MDA-MB-231): kinetics, regulation by estrogen and molecular identity of the transporter. Biochim Biophys Acta. 2004;1664:206–16. CrossRef
- Shennan DB, Thomson J. Inhibition of system L (LAT1/CD98hc) reduces the growth of cultured human breast cancer cells. Oncol Rep. 2008;20:885–9.
- Oka S, Hattori R, Kurosaki F, Toyama M, Williams LA, Yu W, et al. A preliminary study of anti-1-amino-3-18F-fluorocyclobutyl-1-carboxylic acid for the detection of prostate cancer. J Nucl Med. 2007;48:46–55.
- Shoup TM, Olson J, Hoffman JM, Votaw J, Eshima D, Eshima L, et al. Synthesis and evaluation of [18F]1-amino-3-fluorocyclobutane-1-carboxylic acid to image brain tumors. J Nucl Med. 1999;40:331–8.
- Martarello L, McConathy J, Camp VM, Malveaux EJ, Simpson NE, Simpson CP, et al. Synthesis of syn- and anti-1-amino-3-[18F]fluoromethyl-cyclobutane-1-carboxylic acid (FMACBC), potential PET ligands for tumor detection. J Med Chem. 2002;45:2250–9. CrossRef
- Liang Z, Wu T, Lou H, Yu X, Taichman RS, Lau SK, et al. Inhibition of breast cancer metastasis by selective synthetic polypeptide against CXCR4. Cancer Res. 2004;64:4302–8. CrossRef
- Fu OY, Hou MF, Yang SF, Huang SC, Lee WY. Cobalt chloride-induced hypoxia modulates the invasive potential and matrix metalloproteinases of primary and metastatic breast cancer cells. Anticancer Res. 2009;29:3131–8.
- Bouker KB, Skaar TC, Harburger DS, Riggins RB, Fernandez DR, Zwart A, et al. The A4396G polymorphism in interferon regulatory factor 1 is frequently expressed in breast cancer cell lines. Cancer Genet Cytogenet. 2007;175:61–4. CrossRef
- Park SA, Na HK, Kim EH, Cha YN, Surh YJ. 4-hydroxyestradiol induces anchorage-independent growth of human mammary epithelial cells via activation of IkappaB kinase: potential role of reactive oxygen species. Cancer Res. 2009;69:2416–24. CrossRef
- Soule HD, Maloney TM, Wolman SR, Peterson Jr WD, Brenz R, McGrath CM, et al. Isolation and characterization of a spontaneously immortalized human breast epithelial cell line, MCF-10. Cancer Res. 1990;50:6075–86.
- Liang Z, Yoon Y, Votaw J, Goodman M, William L, Shim H. Silencing of CXCR4 blocks breast cancer metastasis. Cancer Res. 2005;65:967–71.
- Shim H, Lau SK, Devi S, Yoon Y, Cho HT, Liang Z. Lower expression of CXCR4 in lymph node metastases than in primary breast cancers: potential regulation by ligand-dependent degradation and HIF-1alpha. Biochem Biophys Res Commun. 2006;346:252–8. CrossRef
- Cappuzzo F, Hirsch FR, Rossi E, Bartolini S, Ceresoli GL, Bemis L, et al. Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. J Natl Cancer Inst. 2005;97:643–55. CrossRef
- McConathy J, Voll RJ, Yu W, Crowe RJ, Goodman MM. Improved synthesis of anti-[18F]FACBC: improved preparation of labeling precursor and automated radiosynthesis. Appl Radiat Isot. 2003;58:657–66. CrossRef
- Yanagida O, Kanai Y, Chairoungdua A, Kim DK, Segawa H, Nii T, et al. Human L-type amino acid transporter 1 (LAT1): characterization of function and expression in tumor cell lines. Biochim Biophys Acta. 2001;1514:291–302. CrossRef
- Tamai S, Masuda H, Ishii Y, Suzuki S, Kanai Y, Endou H. Expression of L-type amino acid transporter 1 in a rat model of liver metastasis: positive correlation with tumor size. Cancer Detect Prev. 2001;25:439–45.
- Kim DK, Ahn SG, Park JC, Kanai Y, Endou H, Yoon JH. Expression of L-type amino acid transporter 1 (LAT1) and 4F2 heavy chain (4F2hc) in oral squamous cell carcinoma and its precusor lesions. Anticancer Res. 2004;24:1671–5.
- Liu XM, Reyna SV, Ensenat D, Peyton KJ, Wang H, Schafer AI, et al. Platelet-derived growth factor stimulates LAT1 gene expression in vascular smooth muscle: role in cell growth. FASEB J. 2004;18:768–70. CrossRef
- Kim DK, Kanai Y, Choi HW, Tangtrongsup S, Chairoungdua A, Babu E, et al. Characterization of the system L amino acid transporter in T24 human bladder carcinoma cells. Biochim Biophys Acta. 2002;1565:112–21. CrossRef
- Christensen HN, Handlogten ME, Lam I, Tager HS, Zand R. A bicyclic amino acid to improve discriminations among transport systems. J Biol Chem. 1969;244:1510–20.
- Nawashiro H, Otani N, Uozumi Y, Ooigawa H, Toyooka T, Suzuki T, et al. High expression of L-type amino acid transporter 1 in infiltrating glioma cells. Brain Tumor Pathol. 2005;22:89–91. CrossRef
- Vansteenkiste JF, Stroobants SG, De Leyn PR, Dupont PJ, Bogaert J, Maes A, et al. Lymph node staging in non-small-cell lung cancer with FDG-PET scan: a prospective study on 690 lymph node stations from 68 patients. J Clin Oncol. 1998;16:2142–9.
- Pieterman RM, van Putten JW, Meuzelaar JJ, Mooyaart EL, Vaalburg W, Koeter GH, et al. Preoperative staging of non-small-cell lung cancer with positron-emission tomography. N Engl J Med. 2000;343:254–61. CrossRef
- Ueda S, Tsuda H, Asakawa H, Omata J, Fukatsu K, Kondo N, et al. Utility of 18F-fluoro-deoxyglucose emission tomography/computed tomography fusion imaging (18F-FDG PET/CT) in combination with ultrasonography for axillary staging in primary breast cancer. BMC Cancer. 2008;8:165. CrossRef
- Brock CS, Meikle SR, Price P. Does fluorine-18 fluorodeoxyglucose metabolic imaging of tumours benefit oncology? Eur J Nucl Med. 1997;24:691–705.
- Stober B, Tanase U, Herz M, Seidl C, Schwaiger M, Senekowitsch-Schmidtke R. Differentiation of tumour and inflammation: characterisation of [methyl-3H]methionine (MET) and O-(2-[18F]fluoroethyl)-L-tyrosine (FET) uptake in human tumour and inflammatory cells. Eur J Nucl Med Mol Imaging. 2006;33:932–9. CrossRef
- Larson SM. Cancer or inflammation? A Holy Grail for nuclear medicine. J Nucl Med. 1994;35:1653–5.
- Bakheet SM, Powe J. Benign causes of [18F]FDG uptake on whole body imaging. Semin Nucl Med. 1998;28:352–8. CrossRef
- Schuster DM, Votaw JR, Nieh PT, Yu W, Nye JA, Master V, et al. Initial experience with the radiotracer anti-1-amino-3-18F-fluorocyclobutane-1-carboxylic acid with PET/CT in prostate carcinoma. J Nucl Med. 2007;48:56–63.
- Schuster DM, Nye JA, Nieh PT, Votaw JR, Halkar RK, Issa MM, et al. Initial experience with the radiotracer anti-1-amino-3-[18F]Fluorocyclobutane-1-carboxylic acid (anti-[ 18F]FACBC) with PET in renal carcinoma. Mol Imaging Biol. 2009;11:434–8. CrossRef
- Yu W, Williams L, Camp VM, Malveaux E, Olson JJ, Goodman MM. Stereoselective synthesis and biological evaluation of syn-1-amino-3-[18F]fluorocyclobutyl-1-carboxylic acid as a potential positron emission tomography brain tumor imaging agent. Bioorg Med Chem. 2009;17:1982–90. CrossRef
- Pegram MD, Pauletti G, Slamon DJ. HER-2/neu as a predictive marker of response to breast cancer therapy. Breast Cancer Res Treat. 1998;52:65–77. CrossRef
- Cobleigh MA, Vogel CL, Tripathy D, Robert NJ, Scholl S, Fehrenbacher L, et al. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol. 1999;17:2639–48.
- Yamasaki S (1978) Estrogen Receptor in Malignant and Benign Breast Tumors and Normal Breast Tissues of Japanese Patients Japanese Journal of Clinical Oncology 8:37–47
- Potential Biomarker of L-type Amino Acid Transporter 1 in Breast Cancer Progression
Nuclear Medicine and Molecular Imaging
Volume 45, Issue 2 , pp 93-102
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- Breast cancer
- Author Affiliations
- 1. Department of Radiology, Emory University School of Medicine, 1365C Clifton Road NE, Atlanta, GA, 30322, USA
- 2. Winship Cancer Institute, Emory University School of Medicine, Atlanta, USA