Overexpression of transforming growth factor alpha overrides the glucocorticoid-mediated suppression of Con8 mammary tumor cell growth in vitro and in vivo.

Abstract

In a preceding paper (D. B. Alexander et al., Cancer Res., 53: 1808-1815, 1993), we demonstrated that the in vitro glucocorticoid inhibition of Con8 mammary tumor cell growth is accompanied by the disruption of a transforming growth factor alpha (TGF-alpha) autocrine loop. This growth suppression response functions in vivo since proliferation of Con8-derived tumors was inhibited in rats treated with the synthetic glucocorticoid, dexamethasone. The effect of dexamethasone on Con8-derived tumor growth was reversible in that tumors rapidly grew at the site of inoculation after discontinuing injections of dexamethasone. To test the in vivo relationship between the glucocorticoid growth suppression response and the TGF-alpha autocrine loop, Con8 cells were transfected with a TGF-alpha expression vector and single cell-derived neomycin-resistant subclones were recovered. [3H]Thymidine incorporation of cultured monolayers of transfected Con8 mammary cells and measurement of tumor diameters in rats revealed that dexamethasone failed to suppress the in vitro proliferation or in vivo tumor growth of Con8-derived cells producing high constitutive levels of secreted TGF-alpha. In contrast, both the in vivo and in vitro growth of Con8 cells transfected with vector controls were fully suppressible by glucocorticoids. Consistent with our in vitro observations, these results demonstrate that the regulation of TGF-alpha production plays a key role in the in vivo glucocorticoid suppression of Con8-derived mammary tumor growth.