University of Groningen, University Medical Center Groningen, Department of Medical Oncology, Groningen, Netherlands.
Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.
J Clin Invest. 2020 Oct 1;130(10):5074-5087. doi: 10.1172/JCI137552.
Hypoxia-inducible factors (HIFs) and the HIF-dependent cancer hallmarks angiogenesis and metabolic rewiring are well-established drivers of breast cancer aggressiveness, therapy resistance, and poor prognosis. Targeting of HIF and its downstream targets in angiogenesis and metabolism has been unsuccessful so far in the breast cancer clinical setting, with major unresolved challenges residing in target selection, development of robust biomarkers for response prediction, and understanding and harnessing of escape mechanisms. This Review discusses the pathophysiological role of HIFs, angiogenesis, and metabolism in breast cancer and the challenges of targeting these features in patients with breast cancer. Rational therapeutic combinations, especially with immunotherapy and endocrine therapy, seem most promising in the clinical exploitation of the intricate interplay of HIFs, angiogenesis, and metabolism in breast cancer cells and the tumor microenvironment.
缺氧诱导因子 (HIFs) 及其依赖的癌症特征——血管生成和代谢重编程，是乳腺癌侵袭性、治疗耐药性和预后不良的明确驱动因素。迄今为止，针对血管生成和代谢中的 HIF 及其下游靶点的靶向治疗在乳腺癌临床治疗中并未取得成功，主要的未解决挑战在于靶标选择、用于预测反应的强大生物标志物的开发，以及对逃逸机制的理解和利用。这篇综述讨论了 HIFs、血管生成和代谢在乳腺癌中的病理生理作用，以及在乳腺癌患者中靶向这些特征所面临的挑战。合理的治疗联合，特别是与免疫疗法和内分泌疗法联合，在临床开发中最有前途，目的是深入研究 HIFs、血管生成和代谢在乳腺癌细胞及其肿瘤微环境中的复杂相互作用。
