Abstract
Fgf4, a member of the fibroblast growth factor family, is frequently amplified in a variety of human cancers, however, its expression in neoplastic tissues is rarely detectable. This makes uncertain its involvement in tumour aetiology, although several in-vitro studies link Fgf4 overexpression to malignant transformation and metastatization of culture cells. We generated a transgenic mouse model in which the whey acidic protein (WAP) promoter directs expression of human Fgf4 to mammary tissues during late pregnancy and throughout lactation, with the purpose of studying the involvement of this growth factor in mammary tumorigenesis. Expression of the transgene was specifically detected in lobular-alveolar cells of lactating mammary glands that, by histological analysis, displayed hyperplastic areas and a disorganized structure. This was accompanied by an increased number of red blood cells and expression, in alveolar epithelial cells, of the vascular endothelial growth factor, which is absent in wild type controls. The most striking effect caused by FGF4 overexpression was on the remodelling of mammary tissue at the end of lactation. Indeed, transgenic animals showed a delayed involution of the gland due to a dramatic reduction in the overall number of apoptotic cells, which are normally present in the organ after weaning. Nevertheless, none of the animals examined developed neoplastic lesions of the mammary gland even after several pregnancies and at old age. Our work represents the first in-vivo demonstration of the anti-apoptotic and angiogenic properties of FGF4.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aging / physiology
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Animals
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Apoptosis*
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Blotting, Western
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Cell Transformation, Neoplastic
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Endothelial Growth Factors / genetics
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Endothelial Growth Factors / metabolism
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Epithelial Cells / metabolism
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Epithelial Cells / pathology
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Female
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Fibroblast Growth Factor 4
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Fibroblast Growth Factors / genetics
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Fibroblast Growth Factors / physiology*
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Gene Expression Regulation
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Humans
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Hyperplasia / blood
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Hyperplasia / genetics
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Hyperplasia / metabolism
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Hyperplasia / pathology*
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Immunohistochemistry
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Lactation
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Lymphokines / genetics
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Lymphokines / metabolism
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Mammary Glands, Animal / abnormalities*
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Mammary Glands, Animal / blood supply
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Mammary Glands, Animal / metabolism
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Mammary Glands, Animal / pathology*
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Mammary Neoplasms, Animal / blood supply
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Mammary Neoplasms, Animal / genetics
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Mammary Neoplasms, Animal / metabolism
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Mammary Neoplasms, Animal / pathology
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Mice
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Mice, Transgenic
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Milk Proteins / analysis
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Milk Proteins / biosynthesis
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Milk Proteins / genetics
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Neovascularization, Pathologic*
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Phenotype
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Pregnancy
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Promoter Regions, Genetic / genetics
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / physiology*
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RNA, Messenger / analysis
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RNA, Messenger / genetics
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Transgenes / genetics
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
Substances
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Endothelial Growth Factors
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FGF4 protein, human
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Fgf4 protein, mouse
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Fibroblast Growth Factor 4
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Lymphokines
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Milk Proteins
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Proto-Oncogene Proteins
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RNA, Messenger
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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whey acidic proteins
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Fibroblast Growth Factors