PMID- 8620493
OWN - NLM
STAT- MEDLINE
DCOM- 19960614
LR  - 20220318
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 56
IP  - 8
DP  - 1996 Apr 15
TI  - Expression of a truncated Int3 gene in developing secretory mammary epithelium 
      specifically retards lobular differentiation resulting in tumorigenesis.
PG  - 1775-85
AB  - Insertional mutation of the Int3 gene, a member of the Notch gene family, is 
      frequently associated with primary mouse mammary tumors induced by the mouse 
      mammary tumor virus (MMTV). A major consequence of these mutations is the 
      production of a shortened 2.4-kb tumor specific Int3 RNA transcript that encodes 
      the entire intracellular domain of the Int3 protein. Previous studies have 
      demonstrated that mammary gland development and function was severely impaired in 
      transgenic mice expressing the truncated Int3 gene product from the MMTV viral 
      promoter. Both mammary ductal growth and secretory lobule development were 
      curtailed in these mice. These results were attributed to a gain of function 
      modification of the Int3 gene, which led to a restriction of cell fate selection 
      in the affected mammary epithelial cells. To confirm and extend these findings, 
      truncated Int3 was expressed from the whey acidic protein (WAP) promoter, the 
      activity of which, unlike that of the MMTV long terminal repeat, is restricted to 
      the secretory mammary epithelial population. In transgenic mice carrying the 
      WAP/Int3 construct, mammary ductal growth was unaffected in virgin females, but 
      growth and differentiation of secretory lobules during gestation was profoundly 
      inhibited. Coincidental with the block in lobular secretory differentiation, 
      mammary dysplasia and tumorigenesis occurred in all breeding females by 25 weeks 
      of age. In nonbreeding WAP/Int3 females, mammary tumor incidence also reached 
      100%, but only after 70 weeks. The WAP/Int3 mammary tumors were highly malignant, 
      and most tumor-bearing females, irrespective of breeding history, developed 
      metastatic lung lesions. These results suggest that WAP promotor-targeted Int3 
      function is associated with mammary secretory cell differentiation and 
      maintenance in this transgenic model. Consistent with the conclusion that 
      WAP-driven truncated Int3 expression influenced only lobular differentiation and 
      not ductal growth and extension during mammary gland development, transplants of 
      WAP/Int3 gland into nontransgenic mammary fat pads produced complete mammary 
      ductal outgrowths in virgin FVB/N mice but failed to develop secretory lobules 
      when the females were impregnated.
FAU - Gallahan, D
AU  - Gallahan D
AD  - Laboratory of Tumor Immunology and Biology, National Cancer Institute, NIH, 
      Bethesda, Maryland 20892, USA.
FAU - Jhappan, C
AU  - Jhappan C
FAU - Robinson, G
AU  - Robinson G
FAU - Hennighausen, L
AU  - Hennighausen L
FAU - Sharp, R
AU  - Sharp R
FAU - Kordon, E
AU  - Kordon E
FAU - Callahan, R
AU  - Callahan R
FAU - Merlino, G
AU  - Merlino G
FAU - Smith, G H
AU  - Smith GH
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (DNA Primers)
RN  - 0 (Milk Proteins)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Receptor, Notch4)
RN  - 0 (Receptors, Cell Surface)
RN  - 0 (Receptors, Notch)
RN  - 0 (Recombinant Proteins)
RN  - 0 (whey acidic proteins)
RN  - 146991-60-8 (Notch4 protein, mouse)
SB  - IM
MH  - Animals
MH  - Base Sequence
MH  - Cell Differentiation
MH  - DNA Primers
MH  - Epithelial Cells
MH  - Epithelium/pathology/physiology
MH  - Female
MH  - *Gene Expression
MH  - Mammary Glands, Animal/cytology/pathology/*physiology
MH  - Mammary Neoplasms, Experimental/genetics/*pathology/*prevention & control
MH  - Mammary Tumor Virus, Mouse
MH  - Mice
MH  - Mice, Inbred Strains
MH  - Mice, Transgenic
MH  - Milk Proteins/biosynthesis/genetics
MH  - Molecular Sequence Data
MH  - Mutagenesis, Insertional
MH  - Polymerase Chain Reaction
MH  - Precancerous Conditions/genetics/pathology
MH  - Pregnancy
MH  - Promoter Regions, Genetic
MH  - Proto-Oncogene Proteins/*biosynthesis/genetics
MH  - Receptor, Notch4
MH  - *Receptors, Cell Surface
MH  - Receptors, Notch
MH  - Recombinant Proteins/biosynthesis
MH  - Transcription, Genetic
EDAT- 1996/04/15 00:00
MHDA- 1996/04/15 00:01
CRDT- 1996/04/15 00:00
PHST- 1996/04/15 00:00 [pubmed]
PHST- 1996/04/15 00:01 [medline]
PHST- 1996/04/15 00:00 [entrez]
PST - ppublish
SO  - Cancer Res. 1996 Apr 15;56(8):1775-85.