Cancer Research Unit, Institute of Biomedical Research, National Autonomous University of Mexico (UNAM)-National Institute of Cancerology, San Fernando Av #22, XVI Section, Mexico City 14080, Mexico.
The Bioinformatics Centre, Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark.
Int J Mol Sci. 2023 Nov 9;24(22):16104. doi: 10.3390/ijms242216104.
Chemoresistance to standard neoadjuvant treatment commonly occurs in locally advanced breast cancer, particularly in the luminal subtype, which is hormone receptor-positive and represents the most common subtype of breast cancer associated with the worst outcomes. Identifying the genes associated with chemoresistance is crucial for understanding the underlying mechanisms and discovering effective treatments. In this study, we aimed to identify genes linked to neoadjuvant chemotherapy resistance in 62 retrospectively included patients with luminal breast cancer. Whole RNA sequencing of 12 patient biopsies revealed 269 differentially expressed genes in chemoresistant patients. We further validated eight highly correlated genes associated with resistance. Among these, solute carrier family 12 member 1 () and glutamate ionotropic AMPA type subunit 4 (), both implicated in ion transport, showed the strongest association with chemoresistance. Notably, expression was downregulated, while protein levels of glutamate receptor 4 (GLUR4), encoded by , were elevated in patients with a worse prognosis. Our results suggest a potential link between gene expression and GLUR4 protein levels with chemoresistance in luminal breast cancer. In particular, GLUR4 protein could serve as a potential target for drug intervention to overcome chemoresistance.
在局部晚期乳腺癌中，特别是在激素受体阳性且与最差预后相关的最常见乳腺癌亚型 luminal 亚型中，常发生对标准新辅助治疗的化疗耐药。确定与化疗耐药相关的基因对于了解潜在机制和发现有效治疗方法至关重要。在这项研究中，我们旨在鉴定 62 例 luminal 乳腺癌患者中与新辅助化疗耐药相关的基因。对 12 例患者活检的全 RNA 测序显示，在化疗耐药患者中有 269 个差异表达的基因。我们进一步验证了与耐药相关的 8 个高度相关的基因。其中，溶质载体家族 12 成员 1 () 和谷氨酸离子型 AMPA 型亚基 4 ()，都与离子转运有关，与耐药性的关联最强。值得注意的是，在预后较差的患者中，表达下调，而编码谷氨酸受体 4 (GLUR4)的基因的蛋白水平升高。我们的研究结果表明，luminal 乳腺癌中 基因表达与 GLUR4 蛋白水平与化疗耐药之间存在潜在联系。特别是，GLUR4 蛋白可能成为克服化疗耐药的药物干预的潜在靶点。
