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Overexpression of Transforming Growth Factor Overrides the Glucocorticoid-mediated Suppression of Con8 Mammary Tumor Cell Growth in Vitro and in Vivo¹

Department of Molecular and Cell Biology and The Cancer Research Laboratory, University of California at Berkeley, Berkeley, California 94720

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 (TGF-) 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- autocrine loop, Con8 cells were transfected with a TGF- 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-. 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- production plays a key role in the in vivo glucocorticoid suppression of Con8-derived mammary tumor growth.

¹ This work was supported by USPHS Grant CA-05388 awarded by the National Cancer Institute and in part by funds awarded from the Lucille P. Markey Program in Biomolecular Structure and Design.

² Recipient of a Postdoctoral Fellowship (Consejo Superior de Investigaciones Cientificas) awarded by the Spanish Government.

³ Predoctoral trainee supported by Developmental Biology Training Grant T2HD-07375 awarded by the NIH.

⁴ Present address: Vincent T. Lombardi Cancer Research Center, Georgetown University Medical Center, Washington, DC.

⁵ To whom requests for reprints should be addressed, at the Department of Molecular and Cell Biology, Box 591 LSA, University of California at Berkeley, Berkeley, CA 94720.

Received 9/17/92. Accepted 2/11/93.

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