A variety of viral and chemical transformed cells and spontaneously arising tumor cells produce a family of growth regulators collectively known as transforming growth factors (TGFs). TGFs are able to confer upon normal, nontransformed cells several properties associated with the transformed phenotype and may be involved in the autocrine growth of these cells. Some of these TGFs, namely alpha-TGF, are structually related to epidermal growth factor (EGF). EGF is required for the growth and survival of normal rodent mammary epithelial cells in a serum-free, hormone-defined medium. However, in contrast, rat mammary tumor cells obtained from chemically-induced rat mammary adenocarcinomas exhibit a diminished response to EGF. This reduced responsiveness to EGF is due to the production of an alpha-TGF-like growth factor, mammary tumor factor (MTF), by these tumor cells. MTF is a heat labile protein whose activity is destroyed by reduction. MTF exists as two species with molecular weights of 68,000 and 6,000 and a pI of 5.2. MTF is mitogenic for normal mammary epithelial cells but not for the tumor cells from which it was derived. Since chemically-induced rat mammary tumors have either an elevated expression or an alteration in structure of the oncogene protein, p21ras, we examined the potential role of TGFs in the transformation of NIH/3T3 cells produced by Kirsten murine sarcoma virus (v-Ki-ras onc gene) and in two cellular revertants (C11 and F2) derived from v-Ki-ras transformed 3T3 cells (DT). The revertant cell lines possess elevated levels of p21ras like DT cells yet fail to grow in soft agar or are tumorigenic in nude mice. However, like DT cells, the revertants lack detectable EGF receptors and product TGFs. Unlike DT cells, the revertants fail to grow in soft agar even in the presence of exogenously supplied TGF. These studies suggest that the lesion(s) in the revertants are distal to the elevated expression of p21ras and production of TGFs and that the elevated production of TGFs is necessary, but may not be entirely sufficient for maintaining the transformed phenotype in ras transformed cells.
