PET Imaging of L-Type Amino Acid Transporter (LAT1) and Cystine-Glutamate Antiporter (x) with [F]FDOPA and [F]FSPG in Breast Cancer Models

Overview

Journal Mol Imaging Biol

Publisher Springer

Specialties Molecular Biology
Radiology

Date 2020 Aug 14

PMID 32789819

Citations 2

Authors

Daniel Krys

Stephanie Mattingly

Darryl Glubrecht

Melinda Wuest

Frank Wuest

Affiliations

Soon will be listed here.

Abstract

Purpose: The present study describes the analysis of amino acid transporters ASCT1, ASCT2, LAT1, and x in breast cancer under normoxic and hypoxic conditions. [F]FDOPA-PET and [F]FSPG-PET were used as imaging biomarkers to probe L-type amino acid transporter (LAT1) and cystine-glutamate antiporter (x) in breast cancer models.

Procedures: LAT1 and x transporters were studied under normoxic and hypoxic conditions with radiotracers [F]FDOPA and [F]FSPG in estrogen receptor-positive (ER+) MCF7 and triple-negative MDA-MB231 cells and in human mammary epithelial MCF10A control cells. Protein expression was analyzed using Western blot and immunohistochemistry.

Results: ASCT1 protein expression levels were comparable in all three cell lines, while noticeable ASCT2 expression levels were only found in MCF10A control cells. Higher LAT1 protein expression was detected in ER+ MCF7 cells. High x protein expression levels were detected in MDA-MB231 cells. Uptake of [F]FDOPA through LAT1 was significantly higher in MCF7 versus MDA-MB231 cells, while the uptake of [F]FSPG through x resulted in the opposite confirming expression and functional differences for both amino acid transporters in different breast cancer models. Hypoxia significantly increased [F]FDOPA uptake in MCF7 cells and [F]FSPG uptake in MDA-MB231 cells. In vivo PET imaging revealed substantially higher tumor uptake of [F]FDOPA in MCF7 tumors as well as [F]FSPG uptake in MDA-MB231 tumors confirming differences detected in vitro.

Conclusions: ER+ breast cancer cells express higher levels of amino acid transporter LAT1, whereas triple-negative breast cancer cells express more x. Cellular uptake and PET imaging experiments with [F]FDOPA and [F]FSPG confirmed functional LAT1 and x expression profiles. There was initial evidence that hypoxia regulates the function of both amino acid transporters in breast cancer. The results further indicated that [F]FDOPA and [F]FSPG are suitable radiotracer to distinguish between ER+ and triple-negative breast cancer types.

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References

DeSantis C, Ma J, Sauer A, Newman L, Jemal A . Breast cancer statistics, 2017, racial disparity in mortality by state. CA Cancer J Clin. 2017; 67(6):439-448. DOI: 10.3322/caac.21412. View

Tevaarwerk A, Gray R, Schneider B, Smith M, Wagner L, Fetting J . Survival in patients with metastatic recurrent breast cancer after adjuvant chemotherapy: little evidence of improvement over the past 30 years. Cancer. 2012; 119(6):1140-8. PMC: 3593800. DOI: 10.1002/cncr.27819. View

Bychkovsky B, Lin N . Imaging in the evaluation and follow-up of early and advanced breast cancer: When, why, and how often?. Breast. 2016; 31:318-324. DOI: 10.1016/j.breast.2016.06.017. View

Groheux D, Cochet A, Humbert O, Alberini J, Hindie E, Mankoff D . ¹⁸F-FDG PET/CT for Staging and Restaging of Breast Cancer. J Nucl Med. 2016; 57 Suppl 1:17S-26S. DOI: 10.2967/jnumed.115.157859. View

Shen B, Huang T, Sun Y, Jin Z, Li X . Revisit 18F-fluorodeoxyglucose oncology positron emission tomography: "systems molecular imaging" of glucose metabolism. Oncotarget. 2017; 8(26):43536-43542. PMC: 5522167. DOI: 10.18632/oncotarget.16647. View

Alvarez J, Belka G, Pan T, Chen C, Blankemeyer E, Alavi A . Oncogene pathway activation in mammary tumors dictates FDG-PET uptake. Cancer Res. 2014; 74(24):7583-98. PMC: 4342047. DOI: 10.1158/0008-5472.CAN-14-1235. View

Kubota K, Yamashita H, Mimori A . Clinical Value of FDG-PET/CT for the Evaluation of Rheumatic Diseases: Rheumatoid Arthritis, Polymyalgia Rheumatica, and Relapsing Polychondritis. Semin Nucl Med. 2017; 47(4):408-424. DOI: 10.1053/j.semnuclmed.2017.02.005. View

Adejolu M, Huo L, Rohren E, Santiago L, Yang W . False-positive lesions mimicking breast cancer on FDG PET and PET/CT. AJR Am J Roentgenol. 2012; 198(3):W304-14. DOI: 10.2214/AJR.11.7130. View

Lieu E, Nguyen T, Rhyne S, Kim J . Amino acids in cancer. Exp Mol Med. 2020; 52(1):15-30. PMC: 7000687. DOI: 10.1038/s12276-020-0375-3. View

10.

Smith B, Schafer X, Ambeskovic A, Spencer C, Land H, Munger J . Addiction to Coupling of the Warburg Effect with Glutamine Catabolism in Cancer Cells. Cell Rep. 2016; 17(3):821-836. PMC: 5108179. DOI: 10.1016/j.celrep.2016.09.045. View

11.

Cha Y, Kim E, Koo J . Amino Acid Transporters and Glutamine Metabolism in Breast Cancer. Int J Mol Sci. 2018; 19(3). PMC: 5877768. DOI: 10.3390/ijms19030907. View

12.

Semenza G . The hypoxic tumor microenvironment: A driving force for breast cancer progression. Biochim Biophys Acta. 2015; 1863(3):382-391. PMC: 4678039. DOI: 10.1016/j.bbamcr.2015.05.036. View

13.

Hamann I, Krys D, Glubrecht D, Bouvet V, Marshall A, Vos L . Expression and function of hexose transporters GLUT1, GLUT2, and GLUT5 in breast cancer-effects of hypoxia. FASEB J. 2018; 32(9):5104-5118. DOI: 10.1096/fj.201800360R. View

14.

Elorza A, Soro-Arnaiz I, Melendez-Rodriguez F, Rodriguez-Vaello V, Marsboom G, de Carcer G . HIF2α acts as an mTORC1 activator through the amino acid carrier SLC7A5. Mol Cell. 2012; 48(5):681-91. DOI: 10.1016/j.molcel.2012.09.017. View

15.

Barollo S, Bertazza L, Watutantrige-Fernando S, Censi S, Cavedon E, Galuppini F . Overexpression of L-Type Amino Acid Transporter 1 (LAT1) and 2 (LAT2): Novel Markers of Neuroendocrine Tumors. PLoS One. 2016; 11(5):e0156044. PMC: 4880303. DOI: 10.1371/journal.pone.0156044. View

16.

Sarikaya I . PET imaging in neurology: Alzheimer's and Parkinson's diseases. Nucl Med Commun. 2015; 36(8):775-81. DOI: 10.1097/MNM.0000000000000320. View

17.

Minn H, Kemppainen J, Kauhanen S, Forsback S, Seppanen M . 18F-fluorodihydroxyphenylalanine in the diagnosis of neuroendocrine tumors. PET Clin. 2014; 9(1):27-36. DOI: 10.1016/j.cpet.2013.08.013. View

18.

Zhang J, Li L, Cheng W . Single incision laparoscopic 90 % pancreatectomy for the treatment of persistent hyperinsulinemic hypoglycemia of infancy. Pediatr Surg Int. 2016; 32(10):1003-7. DOI: 10.1007/s00383-016-3943-9. View

19.

Imperiale A, Sebag F, Vix M, Castinetti F, Kessler L, Moreau F . 18F-FDOPA PET/CT imaging of insulinoma revisited. Eur J Nucl Med Mol Imaging. 2014; 42(3):409-18. DOI: 10.1007/s00259-014-2943-z. View

20.

Koglin N, Mueller A, Berndt M, Schmitt-Willich H, Toschi L, Stephens A . Specific PET imaging of xC- transporter activity using a ¹⁸F-labeled glutamate derivative reveals a dominant pathway in tumor metabolism. Clin Cancer Res. 2011; 17(18):6000-11. DOI: 10.1158/1078-0432.CCR-11-0687. View