Differential expression of the BCAT isoforms between breast cancer subtypes

Shafei, Mai Ahmed; Flemban, Arwa; Daly, Carl; Kendrick, Paul; White, Paul; Dean, Sarah; Qualtrough, David; Conway, Myra E.

Abstract

© 2020, The Author(s). 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.

Citation

Shafei, M. A., Flemban, A., Daly, C., Kendrick, P., White, P., Dean, S., …Conway, M. E. (2021). Differential expression of the BCAT isoforms between breast cancer subtypes. Breast Cancer, 28, 592–607. https://doi.org/10.1007/s12282-020-01197-7

• Journal Article Type: Article
• Acceptance Date: Dec 1, 2020
• Online Publication Date: Dec 24, 2020
• Publication Date: 2021-05
• Deposit Date: Jan 4, 2021
• Publicly Available Date: Jan 15, 2021
• Journal: Breast Cancer
• Print ISSN: 1340-6868
• Electronic ISSN: 1880-4233
• Publisher: Springer (part of Springer Nature)
• Peer Reviewed: Peer Reviewed
• Volume: 28
• Pages: 592–607
• DOI: https://doi.org/10.1007/s12282-020-01197-7
• Keywords: Pharmacology (medical); Oncology; Radiology Nuclear Medicine and imaging; General Medicine
• Public URL: https://uwe-repository.worktribe.com/output/6969537
• Additional Information: Received: 24 June 2020; Accepted: 19 November 2020; First Online: 24 December 2020; : ; : The authors declare that they have no conflict of interest statement.; : Archival human breast cancer tissue samples from surgical resections of breast tumours were obtained from the Bristol Royal Infirmary under ethical approval from NHS Health Research Authority and UWE Ethics Committee (Ref. 11/SW/0127).