© 1992 by Oxford University Press
Journal of the National Cancer Institute, Vol. 84, No. 11, 887-892,
June 3, 1992
© 1992 Oxford University Press
Int-2, an Autocrine and/or Ultra—Short-Range Effector in Transgenic Mammary Tissue Transplants
Howard Hughes Medical Institute and Department of Genetics, Harvard Medical School Boston, Mass
Department of Pathology, School of Medicine, University of California Davis
*Correspondence to present address: David M. Ornitz, M.D., Ph.D., Department of Molecular Biology and Pharmacology, Washington University School of Medicine, 660 S. Euclid St., Box 8103, St. Louis, MO 63110.
Background: Previous studies have shown associations between over-expresion of int-2 messenger RNA (mRNA) and murine mammary tumors and between amplification of the int-2 genomic locus and human breast cancers. The Int-2 protein (fibroblast growth factor 3) is a member of the heparin-binding growth factor family of proteins. The export of these growth factors from cells may depend on the presence of amino terminal sequences containing hydrophobic signal peptides. Although Int-w has a putative signal sequence, it is not known whether or how this protein is secreted from cells. Purpose: Assuming that the Int-2 protein is secreted from mammary epithelial cells in a basolateral direction so that it is available to affect adjacent cells, we investigated whether it acts in a paracrine manner, exerting its effect externally on adjacent cells, or in an autocrine manner, exerting its effect internally within the same cell. Methods: Using in situ hybridization with 35S-labeled RNA antisense probes that specifically detect mRNA coding for the Int-2 protein, we determined the cell-specific localization of int-2 mRNA expression in the mammary gland of transgenic FVB/N mice overexpressing int-2 mRNA. Then we transplanted pieces of mammary epithelial tissue expressing int-2 mRNA into the mammary fat-pad of wild-type, syngeneic animals. The mammary glands of host animals were examined as whole-mounts and as histologic sections 2–6 months after transplantation. In situ hybridization was used to confirm which cells continued to express int-2 mRNA following transplantation. Results: Int-2 mRNA expression in transgenic mice was localized to the mammary epithelial cells. Transplants expressing int-2 mRNA were similar to wild-type transplants in that they had no observable effect on either the growth or the morphology of host mammary epithelium. Abnormal growth occurred only in transplanted tissue expressing int-2 mRNA but not in adjacent host mammary epithelium. Conclusion: Given the limitations of our experimental system and the limited information available to date on the secretion of Int-2 protein, these results suggest that, although the Int-2 protein contains a putative signal pep-tide, it may act primarily as an autocrine or as an ultra—short-range paracrine growth factor in mammary epithelium. [J Natl Cancer Inst 84: 887–892, 1992]
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