Ornitz, DM; Cardiff, RD; Kuo, A; Leder, P. Int-2, an autocrine and/or ultra-short-range effector
in transgenic mammary tissue transplants.
Journal of the National Cancer Institute, 1992 Jun 3, 84(11):887-92. (UI: 92277696)
BACKGROUND:
Previous studies have shown associations between overexpression 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-2 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
peptide, it may act primarily as an autocrine or as an ultra-short-range paracrine growth factor in
mammary epithelium.