TRANSFORMING GROWTH-FACTOR-BETA IN BREAST-CANCER - A WORKING HYPOTHESIS

Transforming Growth Factor-beta (TGF beta) is the most potent known in hibitor of the progression of normal mammary epithelial cells through the cell cycle. During the early stages of breast cancer development, the transformed epithelial cells appear to still be sensitive to TGF b eta-mediated growth arrest, and TGF beta can act as an anti-tumor prom oter. In contrast, advanced breast cancers are mostly refractory to TG F beta-mediated growth inhibition and produce large amounts of TGF bet a, which may enhance tumor cell invasion and metastasis by its effects on extracellular matrix. We postulate that this seemingly paradoxical switch in the responsiveness of tumor cells to TGF beta during progre ssion is the consequence of the activation of the latent TGF beta that is produced and deposited into the tumor microenvironment, thereby dr iving the clonal expansion of TGF beta-resistant tumor cells. While tu mor cells themselves may activate TGF beta, recent observations sugges t that environmental tumor promoters or carcinogens, such as ionizing radiation, can cause stromal fibroblasts to activate TGF beta by epige netic mechanisms. As the biological effects of the anti-estrogen tamox ifen may well be mediated by TGF beta, this model has a number of impo rtant implications for the clinical uses of tamoxifen in the preventio n and treatment of breast cancer. In addition, it suggests a number of novel approaches to the treatment of advanced breast cancer.