Evidence for a positive role of transforming growth factor-beta in human breast cancer cell tumorigenesis.

To determine the biological role of transforming growth factor-beta (TGF-beta) in mammary carcinomas in vivo, estrogen-dependent MCF-7 cells were transfected with a mouse TGF-beta 1 cDNA. Growth characteristics in culture were not altered in the transfected cells. However, the MCF-7/TGF-beta 1 cells formed tumors in ovariectomized athymic mice in the absence of estrogen supplementation. Daily injections of human recombinant TGF-beta 1 supported tumor formation by wild-type MCF-7 cells in castrated nude mice in the absence of exogenous estradiol. In another approach to the same question, the effect of anti-TGF-beta antibodies on tumor formation by estrogen-independent MDA-231 cells was examined. The 2G7 IgG2b (2G7) antibody, which neutralizes TGF-beta 1, -beta 2, and -beta 3, blocked the formation of MDA-231 tumors at the injection site and lung metastases in nude mice. Inoculation of MDA-231 cells inhibited, while injection of 2G7 increased mouse spleen natural killer (NK) activity. 2G7 did not inhibit MDA-231 tumors and metastases in NK-deficient animals. Finally, medium conditioned by MDA-231 cells inhibited lymphocyte-mediated NK activity; this inhibition was abrogated by 2G7, but not by a control IgG2. These data support a positive role for tumor cell TGF-beta in the maintenance and/or progression of mammary carcinoma cells in an intact host.