NCOA1 promotes angiogenesis in breast tumors by simultaneously enhancing both HIF1α- and AP-1-mediated VEGFa transcription.
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.
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
Li
L
Qin
Department of Breast and Thyroid Surgery, Daping Hospital, Third Military Medical University, Chongqing, China.|Breast Disease Center, Southwest Hospital, Third Military Medical University, Chongqing, China.
Yan
Y
Xu
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.|Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX, USA.
Yixiang
Y
Xu
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
Gang
G
Ma
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
Lan
L
Liao
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.|Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China.
Yelin
Y
Wu
Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA.
Yi
Y
Li
Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA.
Xian
X
Wang
Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA.
Xiaosong
X
Wang
Breast Disease Center, Southwest Hospital, Third Military Medical University, Chongqing, China.
Jun
J
Jiang
Department of Pharmacology, Baylor College of Medicine, Houston, TX, USA.
Jin
J
Wang
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.|Institute for Cancer Medicine and College of Basic Medical Sciences, Sichuan Medical University, Luzhou, Sichuan, China.
Jianming
J
Xu
D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007150:Immunohistochemistry; D015674:Mammary Neoplasms, Animal / Q000235:genetics / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008833:Microcirculation; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic; D056920:Nuclear Receptor Coactivator 1 / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014158:Transcription, Genetic; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016760:Proto-Oncogene Proteins c-fos; D018808:Transcription Factor AP-1; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C538859:NCOA1 protein, human; C538861:Ncoa1 protein, mouse; D056920:Nuclear Receptor Coactivator 1
NCOA1; VEGFa; breast cancer; transcriptional regulation