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Production of and Responsiveness to Transforming Growth Factor-ß in Normal and Oncogene-transformed Human Mammary Epithelial Cells¹

Vincent Lombardi Cancer Research Center, Georgetown University Hospital, Washington DC 20007 [E. M. V., M. E. L., R. B. D.]; Department of Zoology, Howard University, Washington DC 20059 [D. W. J.]; Medicine Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892 [S. E. B.]; Lawrence Berkeley Laboratory, Berkeley, California 94720 [M. R. S.]; and Cetus Corporation, Emeryville, California 94608 [R. C., F. M.]

Transforming growth factors-ß (TGFß) are a family of closely related, ubiquitously expressed growth factors with the common properties of induction of growth inhibition and expression of differentiation-related markers in epithelial cells. We investigated the role of TGFß₁ in growth regulation of normal human mammary epithelial cells and in benzo(a)pyrene immortalized sublines further transformed by oncogenes in retroviral vectors. The normal cells were markedly growth inhibited by TGFß₁, produced TGFß in a latent form, and expressed TGFß receptors. In the immortalized cells, both TGFß-induced growth inhibition and TGFß receptor binding were reduced. With the single oncogenes v-Ha-ras, v-mos, and SV40 T, growth sensitivity to TGFß₁ increased, but TGFß production or TGFß receptor expression was not altered. Transformation to full malignancy by both SV40 T and v-Ha-ras led to escape from growth inhibition by TGFß under anchorage-independent, but not anchorage-dependent, conditions without affecting TGFß production or receptor characteristics. Thus, modulation of TGFß growth responsiveness in these normal and oncogene transformed human mammary epithelial cells apparently occurs at a level distal to TGFß receptor binding and is not solely correlated to expression of transforming oncogenes. Further, modulation of TGFß production is not an indicator of malignant transformation in this system.

¹ Supported by NIH Grant CA-24844, and the Office of Energy Research, Office of Health and Environmental Research of the U. S. Department of Energy, (Contract DE-AC03-76SF00098).

² To whom requests for reprints should be addressed, at Vincent Lombardi Cancer Research Center, Georgetown University Hospital, 3900 Reservoir Road NW, Washington DC 20007.

Received 1/ 5/89. Revised 6/ 9/89. Revised 8/16/89. Accepted 8/21/89.

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