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

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Abstract
Transforming Growth Factor-β (TGFβ) is the most potent knowninhibitor of the progression of normal mammary epithelial cells through thecell cycle. During the early stages of breast cancer development, thetransformed epithelial cells appear to still be sensitive toTGFβ-mediated growth arrest, and TGFβ can act as an anti-tumorpromoter. In contrast, advanced breast cancers are mostly refractory toTGFβ-mediated growth inhibition and produce large amounts of TGFβ,which may enhance tumor cell invasion and metastasis by its effects onextracellular matrix. We postulate that this seemingly paradoxical switch inthe responsiveness of tumor cells to TGFβ during progression is theconsequence of the activation of the latent TGFβ that is produced anddeposited into the tumor microenvironment, thereby driving the clonalexpansion of TGFβ-resistant tumor cells. While tumor cells themselvesmay activate TGFβ, recent observations suggest that environmental tumorpromoters or carcinogens, such as ionizing radiation, can cause stromalfibroblasts to activate TGFβ by epigenetic mechanisms. As thebiological effects of the anti-estrogen tamoxifen may well be mediated byTGFβ, this model has a number of important implications for the clinicaluses of tamoxifen in the prevention and treatment of breast cancer. Inaddition, it suggests a number of novel approaches to the treatment ofadvanced breast cancer.

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