PMID- 17114584
OWN - NLM
STAT- MEDLINE
DCOM- 20061222
LR  - 20181113
IS  - 0890-9369 (Print)
IS  - 0890-9369 (Linking)
VI  - 20
IP  - 22
DP  - 2006 Nov 15
TI  - Smad4 is dispensable for normal pancreas development yet critical in progression 
      and tumor biology of pancreas cancer.
PG  - 3130-46
AB  - SMAD4 is inactivated in the majority of pancreatic ductal adenocarcinomas (PDAC) 
      with concurrent mutational inactivation of the INK4A/ARF tumor suppressor locus 
      and activation of the KRAS oncogene. Here, using genetically engineered mice, we 
      determined the impact of SMAD4 deficiency on the development of the pancreas and 
      on the initiation and/or progression of PDAC-alone or in combination with 
      PDAC--relevant mutations. Selective SMAD4 deletion in the pancreatic epithelium 
      had no discernable impact on pancreatic development or physiology. However, when 
      combined with the activated KRAS(G12D) allele, SMAD4 deficiency enabled rapid 
      progression of KRAS(G12D)-initiated neoplasms. While KRAS(G12D) alone elicited 
      premalignant pancreatic intraepithelial neoplasia (PanIN) that progressed slowly 
      to carcinoma, the combination of KRAS(G12D) and SMAD4 deficiency resulted in the 
      rapid development of tumors resembling intraductal papillary mucinous neoplasia 
      (IPMN), a precursor to PDAC in humans. SMAD4 deficiency also accelerated PDAC 
      development of KRAS(G12D) INK4A/ARF heterozygous mice and altered the tumor 
      phenotype; while tumors with intact SMAD4 frequently exhibited 
      epithelial-to-mesenchymal transition (EMT), PDAC null for SMAD4 retained a 
      differentiated histopathology with increased expression of epithelial markers. 
      SMAD4 status in PDAC cell lines was associated with differential responses to 
      transforming growth factor-beta (TGF-beta) in vitro with a subset of SMAD4 
      wild-type lines showing prominent TGF-beta-induced proliferation and migration. 
      These results provide genetic confirmation that SMAD4 is a PDAC tumor suppressor, 
      functioning to block the progression of KRAS(G12D)-initiated neoplasms, whereas 
      in a subset of advanced tumors, intact SMAD4 facilitates EMT and 
      TGF-beta-dependent growth.
FAU - Bardeesy, Nabeel
AU  - Bardeesy N
AD  - Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard 
      Medical School, Boston, Massachusetts 02115, USA. nelbardeesy@partners.org
FAU - Cheng, Kuang-Hung
AU  - Cheng KH
FAU - Berger, Justin H
AU  - Berger JH
FAU - Chu, Gerald C
AU  - Chu GC
FAU - Pahler, Jessica
AU  - Pahler J
FAU - Olson, Peter
AU  - Olson P
FAU - Hezel, Aram F
AU  - Hezel AF
FAU - Horner, James
AU  - Horner J
FAU - Lauwers, Gregory Y
AU  - Lauwers GY
FAU - Hanahan, Douglas
AU  - Hanahan D
FAU - DePinho, Ronald A
AU  - DePinho RA
LA  - eng
GR  - U01 CA084313/CA/NCI NIH HHS/United States
GR  - P01 CA117969/CA/NCI NIH HHS/United States
GR  - P01 CA117969-01/CA/NCI NIH HHS/United States
GR  - 5U01CA84313-08/CA/NCI NIH HHS/United States
GR  - K01 CA104647/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Genes Dev
JT  - Genes & development
JID - 8711660
RN  - 0 (Cdkn2a protein, mouse)
RN  - 0 (Cyclin-Dependent Kinase Inhibitor p16)
RN  - 0 (Smad4 Protein)
RN  - 0 (Smad4 protein, mouse)
RN  - 0 (Transforming Growth Factor beta)
RN  - 0 (Tumor Suppressor Protein p14ARF)
SB  - IM
CIN - Genes Dev. 2006 Nov 15;20(22):3049-53. PMID: 17114578
MH  - Alleles
MH  - Animals
MH  - Carcinoma, Pancreatic Ductal/*pathology
MH  - Cell Differentiation
MH  - Cell Line, Tumor
MH  - Cyclin-Dependent Kinase Inhibitor p16/metabolism
MH  - Disease Progression
MH  - Gene Deletion
MH  - Genes, ras
MH  - Mice
MH  - Pancreas/cytology/*growth & development/pathology
MH  - Pancreatic Neoplasms/*pathology
MH  - Phenotype
MH  - Smad4 Protein/deficiency/*metabolism
MH  - Transforming Growth Factor beta/metabolism
MH  - Tumor Suppressor Protein p14ARF/metabolism
PMC - PMC1635148
EDAT- 2006/11/23 09:00
MHDA- 2006/12/23 09:00
PMCR- 2007/05/15
CRDT- 2006/11/23 09:00
PHST- 2006/11/23 09:00 [pubmed]
PHST- 2006/12/23 09:00 [medline]
PHST- 2006/11/23 09:00 [entrez]
PHST- 2007/05/15 00:00 [pmc-release]
AID - 20/22/3130 [pii]
AID - 10.1101/gad.1478706 [doi]
PST - ppublish
SO  - Genes Dev. 2006 Nov 15;20(22):3130-46. doi: 10.1101/gad.1478706.