Transforming growth factor-β in breast cancer: A working hypothesis

Abstract

Transforming Growth Factor-β (TGFβ) is the most potent known inhibitor 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 TGFβ-mediated growth arrest, and TGFβ can act as an anti-tumor promoter. In contrast, advanced breast cancers are mostly refractory to TGFβ-mediated growth inhibition and produce large amounts of TGFβ, 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 TGFβ during progression is the consequence of the activation of the latent TGFβ that is produced and deposited into the tumor microenvironment, thereby driving the clonal expansion of TGFβ-resistant tumor cells. While tumor cells themselves may activate TGFβ, recent observations suggest that environmental tumor promoters or carcinogens, such as ionizing radiation, can cause stromal fibroblasts to activate TGFβ by epigenetic mechanisms. As the biological effects of the anti-estrogen tamoxifen may well be mediated by TGFβ, this model has a number of important implications for the clinical uses of tamoxifen in the prevention and treatment of breast cancer. In addition, it suggests a number of novel approaches to the treatment of advanced breast cancer.