Transforming growth factor β's role in mammary gland development and carcinogenesis

The pluripotent cytokine transforming growth factor β 1 (TGF-β) can inhibit epithelial proliferation, induce apoptosis and modulate stromal composition. Our studies indicate that epithelial TGF-β production and activity are differentially regulated by estrogen and progesterone during normal mammary gland development and that, in turn, TGF-β regulates epithelial apoptosis and proliferation in a hormone-dependent manner. Our observation that TGF-β activity co-localizes in estrogen receptor-positive cells and that TGF-β depletion increases their frequency and proliferation supports the conclusion that it is a functional determinant of cell fate decisions in response to hormones. Although TGF-β is characterized as a classic tumor suppressor, it can also promote cancer progression. We have shown that the TGF-β signal pathway is rapidly activated as a consequence of ionizing radiation exposure, which is a known breast carcinogen; its role in DNA damage response is not known. We found that mice heterozygous for deletion of the TgfB1 gene fail to undergo cell apoptosis and cell cycle delay in response to DNA damage. Furthermore, TgfB1^+/- mammary epithelial cells fail to appropriately activate p53, indicating that the TGF-β ligand is essential for induction of rapid molecular responses to DNA damage that determine cell fate decisions. Thus, TGF-β action during DNA damage response supports its role as a tumor suppressor. Its loss during carcinogenesis would contribute to genomic instability and promote tumor progression, and in particular may be relevant to the genesis of estrogen receptor-positive tumors.