Reduced GATA3 expression associates with immuno-metabolic alterations and aggressive features in breast cancer

IF 3.7 2区 医学 Q1 PATHOLOGY
Anna KM Sæle, Amalie A Svanøe, Cecilie Askeland, Gøril Knutsvik, Lise M Ingebriktsen, Rasmus OC Humlevik, Anette Heie, Turid Aas, Ingeborg Winge, Karin Collett, Ingunn M Stefansson, Erling A Hoivik, Lars A Akslen, Elisabeth Wik
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Abstract

In breast cancer (BC), the transcription factor GATA3 is linked to estrogen receptor (ER) alpha biology, and its loss is associated with aggressive tumor features. Little is reported about potential roles and implications of GATA3 independent of ER, and possible relationships to the BC tumor microenvironment (TME) have not been much explored. Thus, the discovery of novel biomarkers potentially linked to ER and GATA3 functions and predicting aspects of the TME could significantly improve precision in the management of patient subgroups. We examined GATA3 protein and mRNA expression in a large in-house population-based BC series (n = 837), and in the METABRIC datasets (METABRIC Discovery, n = 997 and METABRIC Validation, n = 995). Associations with primary BC phenotypes, transcriptional programs, TME features, clinical outcomes, and potentially independent roles of GATA3 are reported. We find that low GATA3 expression associates with aggressive features like increased tumor diameter, higher histological grade, triple negative BC, and a basal-like (CK5/6 positive) phenotype. Low GATA3 mRNA expression associated with downregulation of ER-related genes, upregulation of transcriptional signatures reflecting hypoxia, and enrichment of gene sets reflecting tumor cell proliferation, epithelial-mesenchymal transition, and stemness. Low GATA3 protein and mRNA expression both associated with overall reduced BC-specific survival. Notably, low GATA3 expression strongly associated with upregulation of immune checkpoint markers, T-cell activation, and metabolic alterations not previously described in BC. Gene expression patterns underlying GATA3-low tumors, independent of ER status, reflected activation of immunological and metabolic processes. This study suggests that GATA3 might influence the TME independent of ER status. Our results point to metabolic and immunophenotypic alterations in GATA3-low BCs, in particular with T-cell activation and increased expression of immune checkpoints. These findings could be relevant for patient selection in the context of immunotherapies and potential targeting of metabolic pathways.

Abstract Image

乳腺癌中GATA3表达减少与免疫代谢改变和侵袭性特征相关。
在乳腺癌(BC)中,转录因子GATA3与雌激素受体(ER) α生物学有关,其缺失与侵袭性肿瘤特征有关。关于GATA3独立于ER的潜在作用和影响的报道很少,并且对其与BC肿瘤微环境(TME)的可能关系也没有太多的探讨。因此,发现可能与ER和GATA3功能相关的新型生物标志物,并预测TME的各个方面,可以显著提高患者亚组管理的准确性。我们在大量基于内部人群的BC系列(n = 837)和METABRIC数据集(METABRIC Discovery, n = 997和METABRIC Validation, n = 995)中检测了GATA3蛋白和mRNA的表达。报道了GATA3与原发性BC表型、转录程序、TME特征、临床结果和潜在独立作用的关联。我们发现低GATA3表达与肿瘤直径增大、组织学分级高、三阴性BC和基底样(CK5/6阳性)表型等侵袭性特征相关。低GATA3 mRNA表达与er相关基因下调、反映缺氧的转录特征上调以及反映肿瘤细胞增殖、上皮-间质转化和干性的基因集富集有关。低GATA3蛋白和mRNA表达均与bc特异性总体生存率降低相关。值得注意的是,低GATA3表达与免疫检查点标记物上调、t细胞活化和代谢改变密切相关,这些在BC中没有被描述过。低gata3肿瘤的基因表达模式与ER状态无关,反映了免疫和代谢过程的激活。本研究提示GATA3可能独立于ER状态影响TME。我们的研究结果表明,在低gata3的bc中,代谢和免疫表型发生了改变,特别是t细胞活化和免疫检查点的表达增加。这些发现可能与免疫疗法背景下的患者选择和代谢途径的潜在靶向相关。
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来源期刊
Journal of Pathology Clinical Research
Journal of Pathology Clinical Research Medicine-Pathology and Forensic Medicine
CiteScore
7.40
自引率
2.40%
发文量
47
审稿时长
20 weeks
期刊介绍: The Journal of Pathology: Clinical Research and The Journal of Pathology serve as translational bridges between basic biomedical science and clinical medicine with particular emphasis on, but not restricted to, tissue based studies. The focus of The Journal of Pathology: Clinical Research is the publication of studies that illuminate the clinical relevance of research in the broad area of the study of disease. Appropriately powered and validated studies with novel diagnostic, prognostic and predictive significance, and biomarker discover and validation, will be welcomed. Studies with a predominantly mechanistic basis will be more appropriate for the companion Journal of Pathology.
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