ABSTRACT

The glucocorticoid and transforming growth factor- (TGF-) regulation of growth and cell-cell contact was investigated in the Con8 mammary epithelial tumor cell line derived from a 7,12-dimethylbenz()anthracene-induced rat mammary adenocarcinoma. In Con8 cell monolayers cultured on permeable filter supports, the synthetic glucocorticoid, dexamethasone, coordinately suppressed [H]thymidine incorporation, stimulated monolayer transepithelial electrical resistance (TER), and decreased the paracellular leakage of [H]inulin or [C]mannitol across the monolayer. These processes dose dependently correlated with glucocorticoid receptor occupancy and function. Constitutive production of TGF- in transfected cells or exogenous treatment with TGF- prevented the glucocorticoid growth suppression response and disrupted tight junction formation without affecting glucocorticoid responsiveness. Treatment with hydroxyurea or araC demonstrated that de novo DNA synthesis is not a requirement for the growth factor disruption of tight junctions. Immunofluorescence analysis revealed that the ZO-1 tight junction protein is localized exclusively at the cell periphery in dexamethasone-treated cells and that TGF- caused ZO-1 to relocalize from the cell periphery back to a cytoplasmic compartment. Taken together, our results demonstrate that glucocorticoids can coordinately regulate growth inhibition and cell-cell contact of mammary tumor cells and that TGF-, can override both effects of glucocorticoids. These results have uncovered a novel functional ``cross-talk'' between glucocorticoids and TGF- which potentially regulates the proliferation and differentiation of mammary epithelial cells.

FOOTNOTES

*

This research was supported by a grant from the National Institutes of Health (DK-42799). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked ``advertisement'' in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§

To whom correspondence and reprint requests should be addressed: Dept. of Molecular and Cell Biology, Box 591 LSA, University of California, Berkeley, CA 94720.

()

The abbreviations used are: TGF-, transforming growth factor-; EGF, epidermal growth factor; TER, transepithelial electrical resistance; PBS, phosphate-buffered saline; araC, cytosine -D-arabinofuranoside; CAT, chloramphenicol acetyltransferase; GRE, glucocorticoid response element.

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