Summary
Inappropriate expression of a TGFa transgene induced in a majority of multiparous females (transgenic line MT100) the stochastic development of mammary tumors of secretory epithelium; tumors were very rare in virgin MT100 mice. TGFa was highly expressed only in transgenic hyperplasias and tumors. TGFa promoted mammary tumorigenesis in MT100 multiparous females by stimulating secretory epithelial cell growth and prolonged survival during delayed involution.
Citation
G.H. Smith, R. Sharp, E.C. Kordon, C. Jhappan and G. Merlino. 1995.
Transforming growth factor-a promotes mammary tumorigenesis through selective survival and
growth of secretory epithelial cells. Am J Path 147: 1081-1096.
C. Jhappan, C. Stahle, R.N. Harkins, N. Fausto, G.H. Smith and G.T. Merlino. 1990. TGFa overexpression in transgenic mice induces liver neoplasia and abnormal development of the mammary gland and pancreas. Cell 61: 1137-1146.
Background
TGFa is a potent mitogen whose activities are mediated through the
epidermal growth factor receptor. TGFa has been implicated in the pathogenesis of a
variety of malignant diseases, including breast cancer. Mice that overexpress a TGFa
transgene develop liver and mammary tumors, ductular metaplasia and fibrosis in the
pancreas, and a hypertrophic gastropathy resembling MÈnÈtrier's disease in humans. These
mice will soon (1996) be available from the Jackson Laboratory.
Transgene
The expression of a 925 bp human TGFa cDNA was driven by the mouse metallothionein I
promoter and terminated at a human growth hormone polyadenylation signal. TGFa expression
was relatively high in a majority of transgenic mouse tissues. In virgin mammary gland,
transgene expression was lower but detectable.
mouse strain
MT100 was made on a FVB/N genetic background.The transgene was introduced into a FVB/N background.
Delayed involution, resulting in the postlactational survival of unregressed secretory epithelial cells. Development of mammary tumors in multiparous, but not virgin, transgenic females.
Mammary development
a) glandular structures - demonstrated delayed penetration of the fat pad in a related
TGFa transgenic line, MT42.
Ducts
apparently normal
Alveoli
apparently normal, but secretory cells survive involution
Tumors
About 2 of 3 multiparous transgenic females developed mammary tumors by 9
months of age.
Gene expression
TGFa transgene expression is relatively modest in virgin mammary gland, but
becomes abundant in premalignant and malignant lesions of the multiparous gland.
Expression of the transgene was found in epididymis, salicary gland, Harderian gland,
facial mucosal glands and mammary gland. Each of these tissues developed dysplasia and
developmental abnormalities.
Mechanistic implications
These results provide support for the contention that TGFa participates in the development
of human breast cancer, and indicate that TGFa can act not only as a mitogen, but also as
a differentiation factor in mammary epithelium.
key words
transforming growth factor a (TGFa); tumorigenesis; apoptosis;
proliferation; involution.
Submitted by :
Glenn Merlino
Contact for further information: Glenn Merlino (e-mail gmerlino@helix.nih.gov)
contributed November 1995
last update: December 1998