Differential expression of the BCAT isoforms between breast cancer subtypes

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

doi:10.1007/s12282-020-01197-7

Mai Ahmed Shafei, Arwa Flemban + Show 6 more

Open Access

https://doi.org/10.1007/s12282-020-01197-7

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Abstract

BackgroundBiological 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.MethodsUsing 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.ResultsWe 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.ConclusionThe 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.

Highlights

Breast cancer is the most common malignancy in women accounting for almost one in four cancer cases and is responsible for approximately 627,000 deaths each year globally [1]. It is a heterogeneous disease with several distinctive molecular subtypes which are defined by the status of oestrogen receptor (ER), progesterone receptor (PR) and overexpression/amplification of human epidermal growth factor receptor 2 (HER2) [2]
HBCATc expression was found to be significantly associated with the more aggressive HER2 + and luminal B subtype whilst hBCATm and isocitrate dehydrogenase 1 (IDH1) to be significantly associated with luminal A subtype suggesting differential metabolic reliance between these two subtypes
0.022 0.013 0.018 and hBCATm in luminal A breast cancer has been described, which may be mediated by upregulation of the ER-activated sterol response element-binding protein 1 (SREBP1) transcription factor

Summary

Introduction

Breast cancer is the most common malignancy in women accounting for almost one in four cancer cases and is responsible for approximately 627,000 deaths each year globally [1]. Luminal B sub-type has lower expression of several luminal-related genes (such as ESR1 or FOXA1), genomic instability and a higher frequency of TP53 gene mutations associated with a worse prognosis and a higher risk of relapse than luminal A breast cancers [4,5,6] Both luminal A and luminal B are characterised by the expression of the hormone receptors ER and PR, whilst a proportion of luminal B tumours are HER2-enriched [2]. 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. 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

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Conclusion