TGFβ1 and TGFα contrarily affect alveolar survival and tumorigenesis in mouse mammary epithelium

Growth factors and hormones are responsible for development of the mammary gland and can contribute to mammary carcinogenesis. The transforming growth factors (TGF) alpha and beta 1 demonstrate opposing effects on the mammary epithelium. TGF alpha is a mitogen and survival factor for mammary secretory cells and is often upregulated in cancer, while TGF beta 1 may act as a growth suppressor and has been shown to inhibit alveolar development and lactogenesis. To examine the contradistinct effects of TGFa and TGF beta 1 on normal mammary epithelium, we crossed MT-TGF alpha mice with WAP-TGF beta 1 transgenic mice. The newly generated bitransgenic mice failed to nurse their pups and were resistant to mammary tumorigenesis (0% at 12 months of age), compared to single transgenic MT-TGFa in which the majority (65% at 12 months of age) of the mice developed hyperplastic alveolar mammary lesions. Transplantation studies showed that bitransgenic tissue was highly resistant to tumor formation even after multiple pregnancies. WAP-TGF beta 1 mammary transplants often failed to grow and fully fill cleared mammary fat pads upon transplantation. This repression of growth was completely reversed in the bitransgenic implants, which grew as well as normal epithelium upon transplantation. In addition, TGF and bitransgenic TGF alpha/TGF beta 1 mice had reduced rates of apoptosis during involution as compared to wild type and TGF beta 1. These data demonstrate that TGF beta 1 and TGF alpha exhibit opposing effects upon the proliferation and survival of mammary epithelium when expressed alone but when expressed together result in reciprocally suppressive effects upon one another in the context of mammary development and tumorigenesis. (c) 2006 Wiley-Liss, Inc.