Transcriptional Roles of PARP1 in Cancer

Loss of E-cadherin (CDH1), Smad4, and p53 has been shown to play an integral role in gastric, intestinal, and breast cancer formation. Compound conditional knockout mice for Smad4, p53, and E-cadherin were generated to define and compare the roles of these genes in gastric, intestinal, and breast cancer development by crossing with Pdx-1-Cre, Villin-Cre, and MMTV-Cre transgenic mice. Interestingly, gastric adenocarcinoma was significantly more frequent in Pdx-1-Cre;Smad4F/F;Trp53F/F;Cdh1F/+ mice than in Pdx-1-Cre;Smad4F/F;Trp53F/F;Cdh1+/+ mice, demonstrating that Cdh1 heterozygosity accelerates the development and progression of gastric adenocarcinoma, in combination with loss of Smad4 and p53. Pdx-1-Cre;Smad4F/F;Trp53F/F;Cdh1F/+ mice developed gastric adenocarcinomas without E-cadherin expression. However, intestinal and mammary adenocarcinomas with the same genetic background retained E-cadherin expression and were phenotypically similar to mice with both wild-type Cdh1 alleles. Lung metastases were identified in Pdx-1-Cre;Smad4F/F;Trp53F/F;Cdh1F/+ mice, but not in the other genotypes. Nuclear β-catenin accumulation was identified at the invasive tumor front of gastric adenocarcinomas arising in Pdx-1-Cre;Smad4F/F;Trp53F/F;Cdh1F/+ mice. This phenotype was less prominent in mice with intact E-cadherin or Smad4, indicating that the inhibition of β-catenin signaling by E-cadherin or Smad4 downregulates signaling pathways involved in metastases in Pdx-1-Cre;Smad4F/F;Trp53F/F;Cdh1F/+ mice. Knockdown of β-catenin significantly inhibited the migratory activity of Pdx-1-Cre;Smad4F/F;Trp53F/F;Cdh1F/+ cell lines. Thus, loss of E-cadherin and Smad4 cooperates with p53 loss to promote the development and metastatic progression of gastric adenocarcinomas, with similarities to human gastric adenocarcinoma. Implications: This study demonstrates that inhibition of β-catenin is a converging node for the antimetastatic signaling pathways driven by E-cadherin and Smad4 in Pdx-1-Cre;Smad4F/F;Trp53F/F;Cdh1F/+ mice, providing novel insights into mechanisms for gastric cancer metastasis. Mol Cancer Res; 12(8); 1088–99. ©2014 AACR.

[1]  B. Nordlinger,et al.  Linear quantification of lymphoid infiltration of the tumor margin: a reproducible method, developed with colorectal cancer tissues, for assessing a highly variable prognostic factor , 2012, Diagnostic Pathology.

[2]  Joseph T. Roland,et al.  Smad4-mediated signaling inhibits intestinal neoplasia by inhibiting expression of β-catenin. , 2012, Gastroenterology.

[3]  K. Miyazono,et al.  Bone morphogenetic protein-2 and -4 play tumor suppressive roles in human diffuse-type gastric carcinoma. , 2011, The American journal of pathology.

[4]  Y. Eishi,et al.  Synergistic tumour suppressor activity of E-cadherin and p53 in a conditional mouse model for metastatic diffuse-type gastric cancer , 2011, Gut.

[5]  Gerald C. Chu,et al.  SMAD4-dependent barrier constrains prostate cancer growth and metastatic progression , 2011, Nature.

[6]  Yong-jig Cho,et al.  Antimetastatic role of Smad4 signaling in colorectal cancer. , 2010, Gastroenterology.

[7]  P. Guilford,et al.  E-cadherin deficiency initiates gastric signet-ring cell carcinoma in mice and man. , 2009, Cancer research.

[8]  J. Merchant,et al.  Prospective identification of a multilineage progenitor in murine stomach epithelium. , 2007, Gastroenterology.

[9]  Bernhard Schmierer,et al.  TGFβ–SMAD signal transduction: molecular specificity and functional flexibility , 2007, Nature Reviews Molecular Cell Biology.

[10]  Li-hui Wang,et al.  Inactivation of SMAD4 Tumor Suppressor Gene During Gastric Carcinoma Progression , 2007, Clinical Cancer Research.

[11]  T. Joh,et al.  Bone morphogenetic protein 2 induced differentiation toward superficial epithelial cells in the gastric mucosa , 2006, Journal of Gastroenterology.

[12]  Jos Jonkers,et al.  Somatic inactivation of E-cadherin and p53 in mice leads to metastatic lobular mammary carcinoma through induction of anoikis resistance and angiogenesis. , 2006, Cancer cell.

[13]  T. Tsukamoto,et al.  Carcinogenesis in mouse stomach by simultaneous activation of the Wnt signaling and prostaglandin E2 pathway. , 2006, Gastroenterology.

[14]  N. Toribara,et al.  The Adherent Gastric Mucous Layer Is Composed of Alternating Layers of MUC5AC and MUC6 Mucin Proteins , 2004, Digestive Diseases and Sciences.

[15]  Daniel Metzger,et al.  Tissue‐specific and inducible Cre‐mediated recombination in the gut epithelium , 2004, Genesis.

[16]  Y. Yuasa,et al.  BMP-2 modulates the proliferation and differentiation of normal and cancerous gastric cells. , 2004, Biochemical and biophysical research communications.

[17]  B. Jenkins,et al.  Gastric cancer development in mice lacking the SHP2 binding site on the IL-6 family co-receptor gp130. , 2004, Gastroenterology.

[18]  E. Petricoin,et al.  Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. , 2003, Cancer cell.

[19]  C. V. D. van de Velde,et al.  Gastric cancer: epidemiology, pathology and treatment. , 2003, Annals of oncology : official journal of the European Society for Medical Oncology.

[20]  J. Foidart,et al.  Transactivation of Vimentin by β-Catenin in Human Breast Cancer Cells , 2003 .

[21]  J. Foidart,et al.  TRANSACTIVATION OF VIMENTIN BY BETA-CATENIN IN HUMAN BREAST CANCER CELLS , 2003, International Journal of Gynecologic Cancer.

[22]  Birgit Luber,et al.  Differential expression of the epithelial-mesenchymal transition regulators snail, SIP1, and twist in gastric cancer. , 2002, The American journal of pathology.

[23]  R. Kemler,et al.  E-cadherin is a survival factor for the lactating mouse mammary gland , 2002, Mechanisms of Development.

[24]  L. Aaltonen,et al.  Screening E‐cadherin in gastric cancer families reveals germline mutations only in hereditary diffuse gastric cancer kindred , 2002, Human mutation.

[25]  C. Deng,et al.  Generation of Smad4/Dpc4 conditional knockout mice , 2002, Genesis.

[26]  C Caldas,et al.  Incidence of gastric cancer and breast cancer in CDH1 (E-cadherin) mutation carriers from hereditary diffuse gastric cancer families. , 2001, Gastroenterology.

[27]  A. Berns,et al.  Synergistic tumor suppressor activity of BRCA2 and p53 in a conditional mouse model for breast cancer , 2001, Nature Genetics.

[28]  R. Knuechel,et al.  Variable β-catenin expression in colorectal cancers indicates tumor progression driven by the tumor environment , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[29]  C. Caldas,et al.  E-cadherin gene (CDH1) promoter methylation as the second hit in sporadic diffuse gastric carcinoma , 2001, Oncogene.

[30]  Lin Chen,et al.  Haploid loss of the tumor suppressor Smad4/Dpc4 initiates gastric polyposis and cancer in mice , 2000, Oncogene.

[31]  M. Rudnicki,et al.  Amplification of the neu/erbB-2 oncogene in a mouse model of mammary tumorigenesis. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[32]  T. Wang,et al.  Synergistic interaction between hypergastrinemia and Helicobacter infection in a mouse model of gastric cancer. , 2000, Gastroenterology.

[33]  Thomas Kirchner,et al.  β-Catenin Regulates the Expression of the Matrix Metalloproteinase-7 in Human Colorectal Cancer , 1999 .

[34]  Doris Wedlich,et al.  The Wnt/Wg Signal Transducer β-Catenin Controls Fibronectin Expression , 1999, Molecular and Cellular Biology.

[35]  W F Bodmer,et al.  Target genes of beta-catenin-T cell-factor/lymphoid-enhancer-factor signaling in human colorectal carcinomas. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[36]  T. Brabletz,et al.  beta-catenin regulates the expression of the matrix metalloproteinase-7 in human colorectal cancer. , 1999, The American journal of pathology.

[37]  Hiroyuki Miyoshi,et al.  Intestinal Tumorigenesis in Compound Mutant Mice of both Dpc4(Smad4) and Apc Genes , 1998, Cell.

[38]  J. Rossant,et al.  The tumor suppressor gene Smad4/Dpc4 is required for gastrulation and later for anterior development of the mouse embryo. , 1998, Genes & development.

[39]  K M Leung,et al.  Censoring issues in survival analysis. , 1997, Annual review of public health.

[40]  O. Madsen,et al.  Pancreatic-duodenal homeobox 1 -role in gastric endocrine patterning , 1996, Mechanisms of Development.

[41]  P. Chambon,et al.  Gastric Mucosa Abnormalities and Tumorigenesis in Mice Lacking the pS2 Trefoil Protein , 1996, Science.

[42]  G. Tamura,et al.  The sequential accumulation of genetic alterations characteristic of the colorectal adenoma–carcinoma sequence does not occur between gastric adenoma and adenocarcinoma , 1995, The Journal of pathology.

[43]  H. Höfler,et al.  E-cadherin gene mutations provide clues to diffuse type gastric carcinomas. , 1994, Cancer research.