Differential Expression of the BCAT Isoforms Between Breast Cancer Subtypes

Overview

Journal Breast Cancer

Specialty Oncology

Date 2020 Dec 28

PMID 33367952

Citations 6

Authors

Mai Ahmed Shafei

Arwa Flemban

Carl Daly

Paul Kendrick

Paul White

Sarah Dean

David Qualtrough

Myra E Conway

Affiliations

Soon will be listed here.

Abstract

Background: Biological characterisation of breast cancer subtypes is essential as it informs treatment regimens especially as different subtypes have distinct locoregional patterns. This is related to metabolic phenotype, where altered cellular metabolism is a fundamental adaptation of cancer cells during rapid proliferation. In this context, the metabolism of the essential branched-chain amino acids (BCAAs), catalysed by the human branched-chain aminotransferase proteins (hBCAT), offers multiple benefits for tumour growth. Upregulation of the cytosolic isoform of hBCAT (hBCATc), regulated by c-Myc, has been demonstrated to increase cell migration, tumour aggressiveness and proliferation in gliomas, ovarian and colorectal cancer but the importance of the mitochondrial isoform, hBCATm has not been fully investigated.

Methods: Using immunohistochemistry, the expression profile of metabolic proteins (hBCAT, IDH) was assessed between breast cancer subtypes, HER2 + , luminal A, luminal B and TNBC. Correlations between the percentage and the intensity of protein expression/co-expression with clinical parameters, such as hormone receptor status, tumour stage, lymph-node metastasis and survival, were determined.

Results: We show that hBCATc expression was found to be significantly associated with the more aggressive HER2 + and luminal B subtypes, whilst hBCATm and IDH1 associated with luminal A subtype. This was concomitant with better prognosis indicating a differential metabolic reliance between these two subtypes, in which enhanced expression of IDH1 may replenish the α-ketoglutarate pool in cells with increased hBCATm expression.

Conclusion: The cytosolic isoform of BCAT is associated with tumours that express HER2 receptors, whereas the mitochondrial isoform is highly expressed in tumours that are ER + , indicating that the BCAT proteins are regulated through different signalling pathways, which may lead to the identification of novel targets for therapeutic applications targeting dysregulated cancer metabolism.

Citing Articles

Amino acid metabolism in health and disease.

Ling Z, Jiang Y, Ru J, Lu J, Ding B, Wu J Signal Transduct Target Ther. 2023; 8(1):345.

PMID: 37699892 PMC: 10497558. DOI: 10.1038/s41392-023-01569-3.

Branched-chain amino acids catabolism and cancer progression: focus on therapeutic interventions.

Xu E, Ji B, Jin K, Chen Y Front Oncol. 2023; 13:1220638.

PMID: 37637065 PMC: 10448767. DOI: 10.3389/fonc.2023.1220638.

The mechanism of branched-chain amino acid transferases in different diseases: Research progress and future prospects.

Nong X, Zhang C, Wang J, Ding P, Ji G, Wu T Front Oncol. 2022; 12:988290.

PMID: 36119495 PMC: 9478667. DOI: 10.3389/fonc.2022.988290.

Expression of 3-Methylcrotonyl-CoA Carboxylase in Brain Tumors and Capability to Catabolize Leucine by Human Neural Cancer Cells.

Gondas E, Kralova Trancikova A, Baranovicova E, Sofranko J, Hatok J, Kowtharapu B Cancers (Basel). 2022; 14(3).

PMID: 35158853 PMC: 8833481. DOI: 10.3390/cancers14030585.

Nuclear Receptor-Mediated Metabolic Reprogramming and the Impact on HR+ Breast Cancer.

Hussein S, Khanna P, Yunus N, Gatza M Cancers (Basel). 2021; 13(19).

PMID: 34638293 PMC: 8508306. DOI: 10.3390/cancers13194808.

References

Hattori A, Tsunoda M, Konuma T, Kobayashi M, Nagy T, Glushka J . Cancer progression by reprogrammed BCAA metabolism in myeloid leukaemia. Nature. 2017; 545(7655):500-504. PMC: 5554449. DOI: 10.1038/nature22314. View

Zhou W, Feng X, Ren C, Jiang X, Liu W, Huang W . Over-expression of BCAT1, a c-Myc target gene, induces cell proliferation, migration and invasion in nasopharyngeal carcinoma. Mol Cancer. 2013; 12:53. PMC: 3698204. DOI: 10.1186/1476-4598-12-53. View

Asiago V, Alvarado L, Shanaiah N, Gowda G, Owusu-Sarfo K, Ballas R . Early detection of recurrent breast cancer using metabolite profiling. Cancer Res. 2010; 70(21):8309-18. PMC: 2995269. DOI: 10.1158/0008-5472.CAN-10-1319. View

Perou C, Sorlie T, Eisen M, van de Rijn M, Jeffrey S, Rees C . Molecular portraits of human breast tumours. Nature. 2000; 406(6797):747-52. DOI: 10.1038/35021093. View

Kabe Y, Ohmori M, Shinouchi K, Tsuboi Y, Hirao S, Azuma M . Porphyrin accumulation in mitochondria is mediated by 2-oxoglutarate carrier. J Biol Chem. 2006; 281(42):31729-35. DOI: 10.1074/jbc.M604729200. View

Zhang E, Cristofanilli M, Robertson F, Reuben J, Mu Z, Beavis R . Genome wide proteomics of ERBB2 and EGFR and other oncogenic pathways in inflammatory breast cancer. J Proteome Res. 2013; 12(6):2805-17. PMC: 4142215. DOI: 10.1021/pr4001527. View

Raynaud S, Carbuccia N, Colin C, Adelaide J, Mozziconacci M, Metellus P . Absence of R140Q mutation of isocitrate dehydrogenase 2 in gliomas and breast cancers. Oncol Lett. 2012; 1(5):883-884. PMC: 3436391. DOI: 10.3892/ol_00000156. View

Ahn H, Jung S, Kim T, Oh M, Yoon H . Differences in Clinical Outcomes between Luminal A and B Type Breast Cancers according to the St. Gallen Consensus 2013. J Breast Cancer. 2015; 18(2):149-59. PMC: 4490264. DOI: 10.4048/jbc.2015.18.2.149. View

Orecchia R . Tailoring radiotherapy according to cancer subtypes. Breast. 2017; 34 Suppl 1:S91-S94. DOI: 10.1016/j.breast.2017.06.036. View

10.

Shafei M, Forshaw T, Davis J, Flemban A, Qualtrough D, Dean S . BCATc modulates crosstalk between the PI3K/Akt and the Ras/ERK pathway regulating proliferation in triple negative breast cancer. Oncotarget. 2020; 11(21):1971-1987. PMC: 7260123. DOI: 10.18632/oncotarget.27607. View

11.

Thewes V, Simon R, Hlevnjak M, Schlotter M, Schroeter P, Schmidt K . The branched-chain amino acid transaminase 1 sustains growth of antiestrogen-resistant and ERα-negative breast cancer. Oncogene. 2017; 36(29):4124-4134. DOI: 10.1038/onc.2017.32. View

12.

Li Y, Xu S, Mihaylova M, Zheng B, Hou X, Jiang B . AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice. Cell Metab. 2011; 13(4):376-388. PMC: 3086578. DOI: 10.1016/j.cmet.2011.03.009. View

13.

Stoddard B, Dean A, Koshland Jr D . Structure of isocitrate dehydrogenase with isocitrate, nicotinamide adenine dinucleotide phosphate, and calcium at 2.5-A resolution: a pseudo-Michaelis ternary complex. Biochemistry. 1993; 32(36):9310-6. DOI: 10.1021/bi00087a008. View

14.

Kim S, Jung W, Koo J . Differential expression of enzymes associated with serine/glycine metabolism in different breast cancer subtypes. PLoS One. 2014; 9(6):e101004. PMC: 4076239. DOI: 10.1371/journal.pone.0101004. View

15.

Oktyabri D, Ishimura A, Tange S, Terashima M, Suzuki T . DOT1L histone methyltransferase regulates the expression of BCAT1 and is involved in sphere formation and cell migration of breast cancer cell lines. Biochimie. 2016; 123:20-31. DOI: 10.1016/j.biochi.2016.01.005. View

16.

Long J, Li X, Zhang F . Targeting metabolism in breast cancer: How far we can go?. World J Clin Oncol. 2016; 7(1):122-30. PMC: 4734934. DOI: 10.5306/wjco.v7.i1.122. View

17.

Ben-Yosef T, Yanuka O, Halle D, Benvenisty N . Involvement of Myc targets in c-myc and N-myc induced human tumors. Oncogene. 1998; 17(2):165-71. DOI: 10.1038/sj.onc.1201939. View

18.

Shechter I, Dai P, Huo L, Guan G . IDH1 gene transcription is sterol regulated and activated by SREBP-1a and SREBP-2 in human hepatoma HepG2 cells: evidence that IDH1 may regulate lipogenesis in hepatic cells. J Lipid Res. 2003; 44(11):2169-80. DOI: 10.1194/jlr.M300285-JLR200. View

19.

Wang Z, Faddaoui A, Bachvarova M, Plante M, Gregoire J, Renaud M . BCAT1 expression associates with ovarian cancer progression: possible implications in altered disease metabolism. Oncotarget. 2015; 6(31):31522-43. PMC: 4741622. DOI: 10.18632/oncotarget.5159. View

20.

Qie S, Chu C, Li W, Wang C, Sang N . ErbB2 activation upregulates glutaminase 1 expression which promotes breast cancer cell proliferation. J Cell Biochem. 2013; 115(3):498-509. PMC: 4518873. DOI: 10.1002/jcb.24684. View