Transgenic mice overexpressing a dominant-negative mutant type II transforming growth factor beta receptor show enhanced tumorigenesis in the mammary gland and lung in response to the carcinogen 7,12-dimethylbenz-[a]-anthracene.
To test the hypothesis that the transforming growth factor-beta (TGF-beta) 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-beta 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-betas 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-beta system has tumor suppressor activity in the mammary gland and lung.
Böttinger
E P
EP
Laboratories of Chemoprevention, National Cancer Institute, Bethesda, Maryland 20892, USA.
Jakubczak
J L
JL
Haines
D C
DC
Bagnall
K
K
Wakefield
L M
LM
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity*; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D003043:Cocarcinogenesis; D005260:Female; D015870:Gene Expression; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000648:ultrastructure*; D008297:Male; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced* / Q000648:ultrastructure*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism; D019076:Transgenes
D002273:Carcinogens; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D015127:9,10-Dimethyl-1,2-benzanthracene; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II