Reference SummaryGallahan D, Cancer Res 1996 Apr 15;56(8):1775-85

Title

Expression of a truncated Int3 gene in developing secretory mammary epithelium specifically retards lobular differentiation resulting in tumorigenesis.

Authors

Gallahan D; Jhappan C; Robinson G; Hennighausen L; Sharp R; Kordon E; Callahan R; Merlino G; Smith GH

Journal

Cancer Res

Volume

Issue

Year

1996

Pages

1775-85

Abstract

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.

Links

J:33193 – MGI References
8620493 – National Library of Medicine/PubMed

Strain Notes

Strain

Note

FVB/N

Expression of the wild type alleles of the Csnb and Wap genes were reported to be up-regulated in the mammary glands of these mice during lactation.
The wild type allele of the Notch4 gene was reported to be slightly expressed in the mammary glands of virgin mice and in the mammary glands of mice during lactation.

FVB/N-Tg(WapNotch4)10Rnc

Female mice do not produce milk and are unable to nuture their pups.
The "WapInt3" transgene was reported to be expressed in the mammary glands of these mice during lactation.
The wild type allele of the Notch4 gene was reported to be slightly expressed in the mammary glands of these mice during lactation.
The wild type allele of the Notch4 gene was reported to be slightly expressed in the mammary glands of virgin mice.

Models
Strain	Model Name	Organ Affected	Frequency
FVB/N-Tg(WapNotch4)10Rnc	Mammary gland adenocarcinoma - type B	Mammary gland	50 - 100
FVB/N-Tg(WapNotch4)10Rnc	Mammary gland dysplasia	Mammary gland	100
FVB/N-Tg(WapNotch4)10Rnc	Mammary gland hyperplasia	Mammary gland	observed
FVB/N-Tg(WapNotch4)10Rnc	Mammary gland tumor	Mammary gland	0
FVB/N	Mammary gland tumor	Mammary gland	0
FVB/N-Tg(WapNotch4)14Rnc	Mammary gland tumor	Mammary gland	100