NCOA1 Directly Targets M-CSF1 Expression to Promote Breast Cancer Metastasis.
In breast cancer, overexpression of the nuclear coactivator NCOA1 (SRC-1) is associated with disease recurrence and resistance to endocrine therapy. To examine the impact of NCOA1 overexpression on morphogenesis and carcinogenesis in the mammary gland (MG), we generated MMTV-hNCOA1 transgenic [Tg(NCOA1)] mice. In the context of two distinct transgenic models of breast cancer, NCOA1 overexpression did not affect the morphology or tumor-forming capability of MG epithelial cells. However, NCOA1 overexpression increased the number of circulating breast cancer cells and the efficiency of lung metastasis. Mechanistic investigations showed that NCOA1 and c-Fos were recruited to a functional AP-1 site in the macrophage attractant CSF1 promoter, directly upregulating colony-simulating factor 1 (CSF1) expression to enhance macrophage recruitment and metastasis. Conversely, silencing NCOA1 reduced CSF1 expression and decreased macrophage recruitment and breast cancer cell metastasis. In a cohort of 453 human breast tumors, NCOA1 and CSF1 levels correlated positively with disease recurrence, higher tumor grade, and poor prognosis. Together, our results define an NCOA1/AP-1/CSF1 regulatory axis that promotes breast cancer metastasis, offering a novel therapeutic target for impeding this process.
Authors' Affiliations: Department of Molecular and Cellular Biology, Dan L. Duncan Cancer Center, Baylor College of Medicine;
Li
L
Qin
Authors' Affiliations: Department of Molecular and Cellular Biology, Dan L. Duncan Cancer Center, Baylor College of Medicine; Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai;
Ye-Lin
YL
Wu
Authors' Affiliations: Department of Molecular and Cellular Biology, Dan L. Duncan Cancer Center, Baylor College of Medicine;
Michael J
MJ
Toneff
Authors' Affiliations: Department of Molecular and Cellular Biology, Dan L. Duncan Cancer Center, Baylor College of Medicine; Institute for Cancer Medicine and Department of Pathology, Luzhou Medical College, Luzhou, Sichuan, China; and.
Dabing
D
Li
Authors' Affiliations: Department of Molecular and Cellular Biology, Dan L. Duncan Cancer Center, Baylor College of Medicine;
Lan
L
Liao
Authors' Affiliations: Department of Molecular and Cellular Biology, Dan L. Duncan Cancer Center, Baylor College of Medicine;
Xiuhua
X
Gao
Endocrine Oncology Research, Royal College of Surgeons in Ireland, Dublin, Ireland.
Fiona T
FT
Bane
Authors' Affiliations: Department of Molecular and Cellular Biology, Dan L. Duncan Cancer Center, Baylor College of Medicine; Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas;
Jean C-Y
JC
Tien
Authors' Affiliations: Department of Molecular and Cellular Biology, Dan L. Duncan Cancer Center, Baylor College of Medicine; Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas;
Yixiang
Y
Xu
Authors' Affiliations: Department of Molecular and Cellular Biology, Dan L. Duncan Cancer Center, Baylor College of Medicine; Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai;
Zhen
Z
Feng
Authors' Affiliations: Department of Molecular and Cellular Biology, Dan L. Duncan Cancer Center, Baylor College of Medicine; Institute for Cancer Medicine and Department of Pathology, Luzhou Medical College, Luzhou, Sichuan, China; and.
Zhihui
Z
Yang
Authors' Affiliations: Department of Molecular and Cellular Biology, Dan L. Duncan Cancer Center, Baylor College of Medicine;
Yan
Y
Xu
Authors' Affiliations: Department of Molecular and Cellular Biology, Dan L. Duncan Cancer Center, Baylor College of Medicine;
Sarah M
SM
Theissen
Authors' Affiliations: Department of Molecular and Cellular Biology, Dan L. Duncan Cancer Center, Baylor College of Medicine;
Yi
Y
Li
Endocrine Oncology Research, Royal College of Surgeons in Ireland, Dublin, Ireland.
Leonie
L
Young
Authors' Affiliations: Department of Molecular and Cellular Biology, Dan L. Duncan Cancer Center, Baylor College of Medicine; Institute for Cancer Medicine and Department of Pathology, Luzhou Medical College, Luzhou, Sichuan, China; and jxu@bcm.edu.
Jianming
J
Xu
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000556:secondary; D008207:Lymphatic Metastasis; D061986:MCF-7 Cells; D008262:Macrophage Activation / Q000235:genetics / Q000276:immunology; D016173:Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000235:genetics*; D008264:Macrophages / Q000276:immunology; D008324:Mammary Tumor Virus, Mouse; D051379:Mice; D008822:Mice, Transgenic; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D009360:Neoplastic Cells, Circulating / Q000473:pathology; D056920:Nuclear Receptor Coactivator 1 / Q000096:biosynthesis / Q000235:genetics*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering; D018808:Transcription Factor AP-1 / Q000235:genetics
D016760:Proto-Oncogene Proteins c-fos; D034741:RNA, Small Interfering; D018808:Transcription Factor AP-1; D016173:Macrophage Colony-Stimulating Factor; D056920:Nuclear Receptor Coactivator 1