机构：[1]Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA [2]Department of Breast and Thyroid Surgery, Daping Hospital, Third Military Medical University, Chongqing, China [3]Breast Disease Center, Southwest Hospital, Third Military Medical University, Chongqing, China [4]Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX, USA [5]Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China [6]Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA [7]Department of Pharmacology, Baylor College of Medicine, Houston, TX, USA [8]Institute for Cancer Medicine and College of Basic Medical Sciences, Sichuan Medical University, Luzhou, Sichuan, China
Nuclear receptor coactivator 1 (NCOA1) is overexpressed in a subset of breast cancer and its increased expression positively correlates with disease recurrence and metastasis. Although NCOA1 is known to promote breast cancer metastasis through working with multiple transcription factors to upregulate the expression of Twist1, ITGA5, CSF-1, SDF1 and CXCR4, the role of NCOA1 in breast tumor angiogenesis has not been investigated. In this study, we found that the microvascular density (MVD) was significantly decreased and increased in Ncoa1-knockout and NCOA1-overexpressing mammary tumors, respectively, in several breast cancer mouse models. Knockout or knockdown of NCOA1 in breast cancer cell lines also markedly compromised their capability to induce angiogenesis in Matrigel plugs embedded subcutaneously in mice, while this compromised capability could be rescued by VEGFa treatment. At the molecular level, NCOA1 upregulates VEGFa expression in both mouse mammary tumors and cultured breast cancer cells, and it does so by associating with both c-Fos, which is recruited to the AP-1 site at bp -938 of the VEGFa promoter, and HIF1α, which is recruited to the HIF1α-binding element at bp -979 of the VEGFa promoter, to enhance VEGFa transcription. In 140 human breast tumors, high NCOA1 protein correlates with high MVD and patients with both high NCOA1 and high MVD showed significantly shorter survival time. In summary, this study revealed a novel mechanism that NCOA1 potentiates breast cancer angiogenesis through upregulating HIF1α and AP-1-mediated VEGFa expression, which reinforces the rational of targeting NCOA1 in controlling breast cancer progression and metastasis.
基金：
NIH grant CA112403, Cancer Prevention and Research Institute of Texas (CPRIT) grants RP120732-P5 and RP150197, and a subproject of the Susan G. Komen Foundation Promise Grant (PG12221410) to J. Xu. This work was also partially supported by National Natural Science Foundation of China (81472482) and Natural Science Foundation Project of CQ CSTC (cstc2013jcyjA10116) to Y. Xu. The work done by J. Wang was supported by CPRIT (R1104) and Welch Foundation (Q-1798).
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2015]版：
大类|1 区医学
小类|2 区肿瘤学3 区细胞生物学
最新[2023]版：
无
第一作者：
第一作者机构：[1]Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
通讯作者：
通讯机构：[1]Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA [8]Institute for Cancer Medicine and College of Basic Medical Sciences, Sichuan Medical University, Luzhou, Sichuan, China
推荐引用方式(GB/T 7714)：
Qin Li,Xu Yan,Xu Yixiang,et al.NCOA1 promotes angiogenesis in breast tumors by simultaneously enhancing both HIF1α- and AP-1-mediated VEGFa transcription.[J].Oncotarget.2015,6(27):23890-904.doi:10.18632/oncotarget.4341.
APA：
Qin Li,Xu Yan,Xu Yixiang,Ma Gang,Liao Lan...&Xu Jianming.(2015).NCOA1 promotes angiogenesis in breast tumors by simultaneously enhancing both HIF1α- and AP-1-mediated VEGFa transcription..Oncotarget,6,(27)
MLA：
Qin Li,et al."NCOA1 promotes angiogenesis in breast tumors by simultaneously enhancing both HIF1α- and AP-1-mediated VEGFa transcription.".Oncotarget 6..27(2015):23890-904
医学