三阴性乳腺癌的雌激素受体、孕激素受体、人类表皮生长因子受体HER2均为阴性，对激素受体和HER2靶向治疗都不敏感，而且超过30%的患者对化疗耐药，故迫切需要新的治疗方法及其生物学标志。近年来，科学家发现葡萄糖转运蛋白GLUT1高表达于三阴性乳腺癌，并可调节三阴性乳腺癌的葡萄糖代谢，其作用机制尚不明确。
8月21日，英国《自然》旗下《自然通讯》在线发表加拿大多伦多大学、玛格丽特公主癌症中心、多伦多儿童医院、安大略癌症研究所、向量人工智能研究所、麦吉尔大学、古德曼癌症研究中心的研究报告，探讨了GLUT1对三阴性乳腺癌的作用机制。
该研究利用基因技术或靶向药物BAY-876对GLUT1进行抑制，可阻止某些三阴性乳腺癌细胞的生长，具体表现为糖酵解加快和氧化磷酸化减慢。基因表达数据的信号传导通路富集分析表明，转录因子家族E2F信号传导通路功能可能在一定程度上反映氧化磷酸化活性。此外，重要的肿瘤抑制因子视网膜母细胞瘤蛋白RB1水平与三阴性乳腺癌对GLUT1抑制剂的敏感程度密切相关，三阴性乳腺癌RB1阳性细胞对GLUT1抑制剂敏感，而三阴性乳腺癌RB1阴性细胞对GLUT1抑制剂不敏感。
因此，该研究结果表明，GLUT1有望成为三阴性乳腺癌RB1阳性细胞代谢的新靶点，RB1表达水平有望成为GLUT1抑制剂疗效的生物学标志。
相关链接
葡萄糖调节蛋白与肿瘤耐药治疗
糖代谢异常与乳腺癌的关系葡萄糖
Nat Commun. Aug 21. Online ahead of print.
GLUT1 inhibition blocks growth of RB1-positive triple negative breast cancer.
Qin Wu, Wail ba-alawi, Genevieve Deblois, Jennifer Cruickshank, Shili Duan, Evelyne Lima-Fernandes, Jillian Haight, Seyed Ali Madani Tonekaboni, Anne-Marie Fortier, Hellen Kuasne, Trevor D. McKee, Hassan Mahmoud, Michelle Kushida, Sarina Cameron, Nergiz Dogan-Artun, WenJun Chen, Yan Nie, Lan Xin Zhang, Ravi N. Vellanki, Stanley Zhou, Panagiotis Prinos, Bradly G. Wouters, Peter B. Dirks, Susan J. Done, Morag Park, David W. Cescon, Benjamin Haibe-Kains, Mathieu Lupien, Cheryl H. Arrowsmith.
University of Toronto, Toronto, ON, Canada; Princess Margaret Cancer Centre, Toronto, ON, Canada; The Hospital for Sick Children, Toronto, ON, Canada; Ontario Institue for Cancer Research, Toronto, ON, Canada; Vector Institute for Artificial Intelligence, Toronto, ON, Canada; Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada; Benha University, Benha, Egypt.
Triple negative breast cancer (TNBC) is a deadly form of breast cancer due to the development of resistance to chemotherapy affecting over 30% of patients. New therapeutics and companion biomarkers are urgently needed. Recognizing the elevated expression of glucose transporter 1 (GLUT1, encoded by SLC2A1) and associated metabolic dependencies in TNBC, we investigated the vulnerability of TNBC cell lines and patient-derived samples to GLUT1 inhibition. We report that genetic or pharmacological inhibition of GLUT1 with BAY-876 impairs the growth of a subset of TNBC cells displaying high glycolytic and lower oxidative phosphorylation (OXPHOS) rates. Pathway enrichment analysis of gene expression data suggests that the functionality of the E2F pathway may reflect to some extent OXPHOS activity. Furthermore, the protein levels of retinoblastoma tumor suppressor (RB1) strongly correlate with the degree of sensitivity to GLUT1 inhibition in TNBC, where RB1-negative cells are insensitive to GLUT1 inhibition. Collectively, our results highlight a strong and targetable RB1-GLUT1 metabolic axis in TNBC and warrant clinical evaluation of GLUT1 inhibition in TNBC patients stratified according to RB1 protein expression levels.
DOI: 10.1038/s41467-020-18020-8
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