Role of F-box protein βTrcp1 in mammary gland development and tumorigenesis

The F-box protein βTrcp1 controls the stability of several crucial regulators of proliferation and apoptosis, including certain inhibitors of the NF-κB family of transcription factors. Here we show that mammary glands of βTrcp1^-/- female mice display a hypoplastic phenotype, whereas no effects on cell proliferation are observed in other somatic cells. To investigate further the role of βTrcp1 in mammary gland development, we generated transgenic mice expressing human βTrcp1 targeted to epithelial cells under the control of the mouse mammary tumor virus (MMTV) long terminal repeat promoter. Compared to controls, MMTV βTrcp1 mammary glands display an increase in lateral ductal branching and extensive arrays of alveolus-like protuberances. The mammary epithelia of MMTV βTrcp1 mice proliferate more and show increased NF-κB DNA binding activity and higher levels of nuclear NF-κB p65/RelA. In addition, 38% of transgenic mice develop tumors, including mammary, ovarian, and uterine carcinomas. The targeting of βTrcp1 to lymphoid organs produces no effects on these tissues. In summary, our results support the notion that βTrcp1 positively controls the proliferation of breast epithelium and indicate that alteration of βTrcp1 function and expression may contribute to malignant behavior of breast tumors, at least in part through NF-κB transactivation.