Abstract
Growth factors and hormones are responsible for development of the mammary gland and can contribute to mammary carcinogenesis. The transforming growth factors (TGF) α and β1 demonstrate opposing effects on the mammary epithelium. TGFα is a mitogen and survival factor for mammary secretory cells and is often upregulated in cancer, while TGFβ1 may act as a growth suppressor and has been shown to inhibit alveolar development and lactogenesis. To examine the contradistinct effects of TGFα and TGFβ1 on normal mammary epithelium, we crossed MT‐TGFα mice with WAP‐TGFβ1 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‐TGFα 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‐TGFβ1 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 TGFα/TGFβ1 mice had reduced rates of apoptosis during involution as compared to wild type and TGFβ1. These data demonstrate that TGFβ1 and TGFα 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. © 2006 Wiley‐Liss, Inc.