Identification of a Stat3-dependent transcription regulatory network involved in metastatic progression.

High levels of activated Stat3 are often found in human breast cancers and can correlate with poor patient outcome. We employed an activated ErbB2 mouse model of breast cancer to investigate the in vivo role of Stat3 in mammary tumor progression and found that Stat3 does not alter mammary tumor initiation but dramatically affects metastatic progression. Four-fold fewer animals exhibited lung metastases in the absence of Stat3 and a 12-fold reduction in the number of lung lesions was observed in animals bearing Stat3-null tumors when compared with the wild-type cohort. The decreased malignancy in Stat3-deficient tumors is attributed to a reduction in both angiogenic and inflammatory responses associated with a Stat3-dependent transcriptional cascade involving CCAAT/enhancer binding protein delta.

[1]  C. Watson,et al.  Stat3 and the Inflammation/Acute Phase Response in Involution and Breast Cancer , 2009, Journal of Mammary Gland Biology and Neoplasia.

[2]  C. Watson Immune cell regulators in mouse mammary development and involution. , 2009, Journal of animal science.

[3]  B. O’Malley,et al.  Disruption of the SRC-1 gene in mice suppresses breast cancer metastasis without affecting primary tumor formation , 2009, Proceedings of the National Academy of Sciences.

[4]  T. Pawson,et al.  ShcA signalling is essential for tumour progression in mouse models of human breast cancer , 2008, The EMBO journal.

[5]  J. Turkson,et al.  STAT3 as a target for inducing apoptosis in solid and hematological tumors , 2008, Cell Research.

[6]  Yingjie Zhang,et al.  The mouse C/EBPδ gene promoter is regulated by STAT3 and Sp1 transcriptional activators, chromatin remodeling and c‐Myc repression , 2007, Journal of cellular biochemistry.

[7]  D. Frank STAT3 as a central mediator of neoplastic cellular transformation. , 2007, Cancer letters.

[8]  J. Pollard,et al.  Macrophages regulate the angiogenic switch in a mouse model of breast cancer. , 2006, Cancer research.

[9]  Rainer Breitling,et al.  RankProd: a bioconductor package for detecting differentially expressed genes in meta-analysis , 2006, Bioinform..

[10]  C. Chai,et al.  Altered p-STAT3 (tyr705) expression is associated with histological grading and intratumour microvessel density in hepatocellular carcinoma , 2006, Journal of Clinical Pathology.

[11]  M. Hou,et al.  STAT3 ser727 phosphorylation and its association with negative estrogen receptor status in breast infiltrating ductal carcinoma , 2006, International journal of cancer.

[12]  T. Bito,et al.  Stat3 activation is required for cell proliferation and tumorigenesis but not for cell viability in cutaneous squamous cell carcinoma cell lines , 2006, Experimental dermatology.

[13]  T. Freeman,et al.  The genes induced by signal transducer and activators of transcription (STAT)3 and STAT5 in mammary epithelial cells define the roles of these STATs in mammary development. , 2006, Molecular endocrinology.

[14]  Meenakshi Singh,et al.  Remodeling of the mammary microenvironment after lactation promotes breast tumor cell metastasis. , 2006, The American journal of pathology.

[15]  Alan Cantor,et al.  Activation of Stat3 in Primary Tumors from High-Risk Breast Cancer Patients Is Associated with Elevated Levels of Activated Src and Survivin Expression , 2006, Clinical Cancer Research.

[16]  M. Raffeld,et al.  C/EBPδ is a crucial regulator of pro-apoptotic gene expression during mammary gland involution , 2005, Development.

[17]  Peter Carmeliet,et al.  VEGF as a Key Mediator of Angiogenesis in Cancer , 2005, Oncology.

[18]  Jiayuh Lin,et al.  Evaluation of potential Stat3-regulated genes in human breast cancer. , 2005, Biochemical and biophysical research communications.

[19]  G. Semenza,et al.  Targeting Stat3 blocks both HIF-1 and VEGF expression induced by multiple oncogenic growth signaling pathways , 2005, Oncogene.

[20]  W. Muller,et al.  Targeted disruption of beta1-integrin in a transgenic mouse model of human breast cancer reveals an essential role in mammary tumor induction. , 2004, Cancer cell.

[21]  W. Gerald,et al.  Requirement of matrix metalloproteinase-9 for the transformation of human mammary epithelial cells by Stat3-C. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[22]  Shan Wang,et al.  Constitutive activation of Stat3 signaling pathway in human colorectal carcinoma. , 2004, World journal of gastroenterology.

[23]  F. Ali-Osman,et al.  Stat3 activation regulates the expression of matrix metalloproteinase-2 and tumor invasion and metastasis , 2004, Oncogene.

[24]  Hua Yu,et al.  The STATs of cancer — new molecular targets come of age , 2004, Nature Reviews Cancer.

[25]  Joanna S Morris,et al.  Involution of the mouse mammary gland is associated with an immune cascade and an acute-phase response, involving LBP, CD14 and STAT3 , 2003, Breast Cancer Research.

[26]  Terry Speed,et al.  Normalization of cDNA microarray data. , 2003, Methods.

[27]  Rafael A Irizarry,et al.  Exploration, normalization, and summaries of high density oligonucleotide array probe level data. , 2003, Biostatistics.

[28]  Chia-Hung Chou,et al.  Interleukin-6 promotes cervical tumor growth by VEGF-dependent angiogenesis via a STAT3 pathway , 2003, Oncogene.

[29]  Z. Ren,et al.  ErbB-2 Activates Stat3α in a Src- and JAK2-dependent Manner* , 2002, The Journal of Biological Chemistry.

[30]  D. Levy,et al.  Deletion of Stat3 blocks mammary gland involution and extends functional competence of the secretory epithelium in the absence of lactogenic stimuli. , 2002, Endocrinology.

[31]  J. Grandis,et al.  STAT3 activation abrogates growth factor dependence and contributes to head and neck squamous cell carcinoma tumor growth in vivo. , 2002, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[32]  L. Ellis,et al.  Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis , 2002, Oncogene.

[33]  R. Jove,et al.  Requirement of Stat3 signaling for HGF/SF-Met mediated tumorigenesis , 2002, Oncogene.

[34]  Jean Yee Hwa Yang,et al.  Analysis of CDNA Microarray Images , 2001, Briefings Bioinform..

[35]  J. Turkson,et al.  Phosphotyrosyl Peptides Block Stat3-mediated DNA Binding Activity, Gene Regulation, and Cell Transformation* , 2001, The Journal of Biological Chemistry.

[36]  Jiayuh Lin,et al.  Inhibition of constitutively active Stat3 suppresses growth of human ovarian and breast cancer cells , 2001, Oncogene.

[37]  V. Poli,et al.  Essential Role of STAT3 in the Control of the Acute-Phase Response as Revealed by Inducible Gene Activation in the Liver , 2001, Molecular and Cellular Biology.

[38]  Simon C Watkins,et al.  Constitutive activation of Stat3 signaling abrogates apoptosis in squamous cell carcinogenesis in vivo. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[39]  J. Darnell,et al.  Stat3 as an Oncogene , 1999, Cell.

[40]  R. Badolato,et al.  New Insights into the Biology of the Acute Phase Response , 1999, Journal of Clinical Immunology.

[41]  P. D’Eustachio,et al.  Essential role of STAT3 for embryonic stem cell pluripotency. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[42]  J. Darnell,et al.  Stat3 Activation Is Required for Cellular Transformation by v-src , 1998, Molecular and Cellular Biology.

[43]  Peter F. Johnson,et al.  Interleukin-6-Specific Activation of the C/EBPδ Gene in Hepatocytes Is Mediated by Stat3 and Sp1 , 1998, Molecular and Cellular Biology.

[44]  R. Jove,et al.  Constitutive activation of Stat3 in fibroblasts transformed by diverse oncoproteins and in breast carcinoma cells. , 1997, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[45]  B. Ray,et al.  Serum amyloid A gene expression under acute-phase conditions involves participation of inducible C/EBP-beta and C/EBP-delta and their activation by phosphorylation , 1994, Molecular and cellular biology.

[46]  R. Dhir Stat3 Promotes Metastatic Progression of Prostate Cancer , 2009 .

[47]  住田 奈穂子 Stat3 activation is required for cell proliferation and tumorigenesis but not for cell viability in cutaneous squamous cell carcinoma cell lines , 2006 .

[48]  Greg Finak,et al.  BIAS: Bioinformatics Integrated Application Software , 2004 .

[49]  ShanWang,et al.  Constitutive activation of Stat3 signaling pathway in human colorectal carcinoma , 2004 .

[50]  Gabriella,et al.  Essential role of STAT3 in the control of the acute-phase response as revealed by inducible gene inactivation [correction of activation] in the liver. , 2001, Molecular and cellular biology.