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[Cancer Research 57, 5564-5570, December 15, 1997]
© 1997 American Association for Cancer Research
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Transgenic Mice Overexpressing a Dominant-negative Mutant Type II Transforming Growth Factor ß Receptor Show Enhanced Tumorigenesis in the Mammary Gland and Lung in Response to the Carcinogen 7,12-Dimethylbenz-[a]-anthracene

Erwin P. Böttinger1, John L. Jakubczak, Diana C. Haines, Kerri Bagnall and Lalage M. Wakefield2

Laboratories of Chemoprevention [E. P. B., K. B., L. M. W.] and Molecular Biology [J. L. J.], National Cancer Institute, Bethesda, Maryland 20892, and Pathology/Histotechnology Laboratory, Science Applications International Corp., National Cancer Institute, Frederick Cancer Research and Development Center, Frederick, Maryland 21702 [D. C. H.]

To test the hypothesis that the transforming growth factor-ß (TGF-ß) system has tumor suppressor activity in the mammary gland, we have generated transgenic mice overexpressing a dominant-negative mutant form of the type II TGF-ß receptor, under the control of the mouse mammary tumor virus-long terminal repeat. High-level expression of the transgene was observed in the mammary and salivary glands, with lower expression in the lung, spleen, and testis. Older nulliparous transgenic mice (9–17 months) showed a marked increase in the incidence and degree of lobulo-alveolar side-branching in the mammary glands when compared to wild-type littermates (24.8% of glands examined histologically versus 14.4%; P = 0.004), suggesting a role for endogenous TGF-ßs in regulating development or maintenance of mammary alveoli. Spontaneous tumorigenesis was unchanged in the transgenic mice. However, following initiation with the carcinogen 7,12-dimethylbenz[a]anthracene, the transgenic group showed a significant increase in the incidence and multiplicity of mammary tumors when compared with wild-type littermates (40% incidence in transgenic mice versus 22% for wild-type, with 4 of 25 transgenics developing multiple mammary tumors versus 0 of 27 wild-type; P = 0.03). An early increase in the incidence of lung tumors was also observed in transgenic mice, but no difference between genotype groups was seen in the incidence of tumors in tissues in which the transgene is not expressed. The data show that the endogenous TGF-ß system has tumor suppressor activity in the mammary gland and lung.

1 Present address: Renal Division, U617, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461-1602.

2 To whom requests for reprints should be addressed, at Laboratory of Chemoprevention, Building 41, Room C629, 41 Library Drive, MSC 5055, Bethesda, MD 20892-5055. Phone: (301) 496-8351; Fax: (301) 496-8395; E-mail: wakefiel@dce41.nci.nih.gov.

Received 7/ 7/97. Accepted 10/15/97.




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[Abstract] [Full Text] [PDF]

Home page
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[Abstract] [Full Text] [PDF]

Home page
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[Abstract] [Full Text] [PDF]

Home page
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[Abstract] [Full Text] [PDF]

Home page
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Home page
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[Abstract] [Full Text] [PDF]

Home page
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[Abstract] [Full Text] [PDF]

Home page
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[Abstract] [Full Text] [PDF]

Home page
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Cancer Res., June 1, 1999; 59(12): 2861 - 2868.
[Abstract] [Full Text] [PDF]

Home page
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[Abstract] [Full Text] [PDF]


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