Samanta Debangshu, Gilkes Daniele M, Chaturvedi Pallavi, Xiang Lisha, Semenza Gregg L
Vascular Program, Institute for Cell Engineering, McKusick-Nathans Institute of Genetic Medicine, and.
Vascular Program, Institute for Cell Engineering, McKusick-Nathans Institute of Genetic Medicine, and Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
Proc Natl Acad Sci U S A. 2014 Dec 16;111(50):E5429-38. doi: 10.1073/pnas.1421438111. Epub 2014 Dec 1.
Triple negative breast cancers (TNBCs) are defined by the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 expression, and are treated with cytotoxic chemotherapy such as paclitaxel or gemcitabine, with a durable response rate of less than 20%. TNBCs are enriched for the basal subtype gene expression profile and the presence of breast cancer stem cells, which are endowed with self-renewing and tumor-initiating properties and resistance to chemotherapy. Hypoxia-inducible factors (HIFs) and their target gene products are highly active in TNBCs. Here, we demonstrate that HIF expression and transcriptional activity are induced by treatment of MDA-MB-231, SUM-149, and SUM-159, which are human TNBC cell lines, as well as MCF-7, which is an ER(+)/PR(+) breast cancer line, with paclitaxel or gemcitabine. Chemotherapy-induced HIF activity enriched the breast cancer stem cell population through interleukin-6 and interleukin-8 signaling and increased expression of multidrug resistance 1. Coadministration of HIF inhibitors overcame the resistance of breast cancer stem cells to paclitaxel or gemcitabine, both in vitro and in vivo, leading to tumor eradication. Increased expression of HIF-1α or HIF target genes in breast cancer biopsies was associated with decreased overall survival, particularly in patients with basal subtype tumors and those treated with chemotherapy alone. Based on these results, clinical trials are warranted to test whether treatment of patients with TNBC with a combination of cytotoxic chemotherapy and HIF inhibitors will improve patient survival.
三阴性乳腺癌（TNBC）的定义是缺乏雌激素受体（ER）、孕激素受体（PR）以及人表皮生长因子受体2表达，其治疗采用细胞毒性化疗药物，如紫杉醇或吉西他滨，持久缓解率低于20%。TNBC富含基底亚型基因表达谱以及乳腺癌干细胞，这些干细胞具有自我更新、肿瘤起始特性以及对化疗的抗性。缺氧诱导因子（HIF）及其靶基因产物在TNBC中高度活跃。在此，我们证明，用紫杉醇或吉西他滨处理人TNBC细胞系MDA-MB-231、SUM-149和SUM-159以及ER(+)/PR(+)乳腺癌细胞系MCF-7后，HIF表达和转录活性会被诱导。化疗诱导的HIF活性通过白细胞介素-6和白细胞介素-8信号通路使乳腺癌干细胞群体富集，并增加多药耐药蛋白1的表达。在体外和体内，联合使用HIF抑制剂可克服乳腺癌干细胞对紫杉醇或吉西他滨的抗性，从而根除肿瘤。乳腺癌活检中HIF-1α或HIF靶基因表达增加与总生存期缩短相关，尤其是在基底亚型肿瘤患者以及仅接受化疗的患者中。基于这些结果，有必要开展临床试验，以检验TNBC患者联合使用细胞毒性化疗药物和HIF抑制剂进行治疗是否能提高患者生存率。
