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Glucocorticoids Coordinately Disrupt a Transforming Growth Factor Autocrine Loop and Suppress the Growth of 13762NF-derived Con8 Rat Mammary Adenocarcinoma Cells¹

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

We have demonstrated previously that the synthetic glucocorticold dexamethasone suppresses the growth of Con8 rat mammary tumor cells, which are derived from the 13762NF transplantable, hormone-responsive rat mammary adenocarcinoma. Dexamethasone inhibited [³H]thymidine incorporation into Con8 cells at high cell density under both serum and serum-free conditions. Fractionation in nonreducing sodium dodecyl sulfate-polyacrylamide gels of proteins secreted from dexamethasone-treated and untreated Con8 mammary tumor cells revealed two size classes of glucocorticoid inhibited mitogenic activities; a larger M_r 27,000–33,000 and a smaller M_r 5,000–12,000 activity. Both size classes of mitogens restimulated the growth of glucocorticoid-suppressed Con8 cells suggesting that they can act in an autocrine fashion. The smaller mitogen was identified as transforming growth factor (TGF-) since this activity competed with ¹²⁵I-epidermal growth factor (EGF) for EGF receptor binding and was selectively immunodepleted with monoclonal TGF- antibodies but not with EGF antibodies. Western blots and radioreceptor assay of Con8-secreted proteins revealed that glucocorticoids inhibited the production of a M_r 5500 immunoreactive TGF- protein by 10-fold. Consistent with a steroid effect on the level of TGF- production, rather than on its activity, the specific mitogenic activities of the TGF-s secreted by dexamethasone-treated and untreated Con8 cells were identical to that of recombinant human TGF-. Treatment of intact cells with suramin, which dissociates ligand-receptor complexes, revealed that the EGF receptor-mediated mitogenic response is functional in both glucocorticoid-treated and untreated cells. Taken together, our results demonstrate that glucocorticoids suppress Con8 mammary tumor cell growth and disrupt a potential TGF- autocrine loop which results in a dramatic reduction in the level of extracellular TGF-.

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

³ Postdoctoral fellow supported by a Postdoctoral Fellowship (Consejo Superior de Investigaciones Cientificas) awarded by the Spanish Government.

⁴ 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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