Mechanisms for the escape of breast cancer cells from normal growth controls are being evaluated, both in human and rodent tumor model systems. Two growth promoting and two growth inhibiting activities, present in and made by mammary tissues, have been detected. One of these, MDGFI, a human factor, was found to be secreted into the growth medium by primary cultures of normal, benign and malignant human mammary epithelium. On average, the malignant cells made about three times as much MDGFI as did the normal cells. A second growth promoter, transforming growth factor alpha (TGF alpha) was also made by both normal cells and by carcinoma in situ. In rodent tissues, a change in TGF alpha production was found as a function of the stage of progression of the tumors. Normal cells produced readily detectable TGF alpha levels, whereas production by adenocarcinomas was significantly more. In the most advanced tumors, those with high metastatic potential, TGF alpha production was nearly zero. These results were confirmed both by radioimmunoassay and by Northern blot analysis of poly A+ mRNA. In vivo and in vitro studies demonstrated that estrogens regulated the production of TGF alpha by rodent mammary adenocarcinomas, a finding consistent with the depletion of TGF alpha mRNA following ovariectomy. TGF beta one growth inhibitor made by mammary tissues, was found by bioassay, and by Northern blot hybridization to be produced in equivalent amounts by both normal and malignant rodent and human mammary epithelium. A second inhibitor, a 13 Kd acidic protein, was found to be high in normal but low in malignant mammary cells. This factor has been purified 5000 fold and partial sequence determined. Nanogram amounts inhibit normal and malignant mammary cell growth in vitro and also dramatically lower the production of extracellular matrix proteins.
