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Transforming Growth Factor ß: Potential Autocrine Growth Inhibitor of Estrogen Receptor-negative Human Breast Cancer Cells¹

Department of Medical Oncology, University of Texas Health Science Center, San Antonio, Texas 78284-7884

Transforming growth factor ß (TGFß), a two-subunit M_r 25,000 polypeptide, inhibits growth of several epithelial human cancer cell lines and has been proposed as an autocrine growth inhibitor. TGFß activity has been found in conditioned media from some breast cancer cell lines, and TGFß mRNA has been detected in breast cancer cell lines and human breast cancer specimens. In the present study we attempted to characterize the interaction of TGFß with breast cancer cells by examining the biological activity, receptor binding, and secretion of this polypeptide by a panel of estrogen receptor (ER)-positive and ER-negative human breast cancer cell lines. Growth of the four ER-negative lines, MDA231, MDA330, HS578T, and BT20, was exquisitely sensitive to TGFß. Dose-dependent inhibition of monolayer growth, anchorage-independent growth, and of [³H]thymidine incorporation was observed with TGFß concentrations ranging from 1 to 100 pM. Growth of the four ER-positive lines, T47D, ZR75-1, and two MCF7 lines from different laboratories, was unaffected by similar concentrations of TGFß. In receptor-binding studies using ¹²⁵I-TGFß, the four ER-negative lines exhibited specific high affinity TGFß receptors. Binding was a time- and temperature-dependent process. Scatchard analysis of the binding data showed between 2800 and 12900 receptor sites per cell and a K_d between 29 and 160 pM. Epidermal growth factor, insulin, insulin-like growth factors I and II, and transforming growth factor did not compete for ¹²⁵I-TGFß binding. Chemical cross-linking studies with ER-negative breast cancer cells revealed three specific TGFß receptors with molecular weights approximating 400,000, 92,000, and 69,000. The four ER-positive lines had no detectable TGFß binding. Using a radioreceptor assay with A549 cells and a NRK bioassay, TGFß activity was detectable in the conditioned media from the four ER-negative cell lines; media from the ER-positive lines had low levels of TGFß activity. In summary, ER-negative, estrogen-independent cultured human breast cancer cells have receptors for, are inhibited by, and secrete TGFß activity, suggesting the possibility that this polypeptide may function as an autocrine growth inhibitor or as a paracrine growth factor for tumor stromal cells.

¹ This work was supported in part by USPHS Grant CA09434 (C. L. A.), American Cancer Society Grant CH162D (D. D. V. H.), USPHS Grant CA30251 (C. K. O.), and a VA Career Development Award (C. L. A.). This work was presented in part at the annual meeting of the American Association for Cancer Research, Inc., held in May 1987 in Atlanta, GA.

² Recipient of an Associate Investigator Career Development Award from the Veterans Administration.

³ To whom requests for reprints should be addressed.

Received 10/26/87. Revised 4/ 8/88. Accepted 4/12/88.

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