TGFbeta1 and TGFalpha 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 beta1 demonstrate opposing effects on the mammary epithelium. TGFalpha is a mitogen and survival factor for mammary secretory cells and is often upregulated in cancer, while TGFbeta1 may act as a growth suppressor and has been shown to inhibit alveolar development and lactogenesis. To examine the contradistinct effects of TGFalpha and TGFbeta1 on normal mammary epithelium, we crossed MT-TGFalpha mice with WAP-TGFbeta1 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-TGFalpha 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-TGFbeta1 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 TGFalpha/TGFbeta1 mice had reduced rates of apoptosis during involution as compared to wild type and TGFbeta1. These data demonstrate that TGFbeta1 and TGFalpha 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.