Role of F-Box Protein Trcp1 in Mammary Gland Development and Tumorigenesis

The F-box protein Trcp1 controls the stability of several crucial regulators of proliferation and apoptosis, including certain inhibitors of the NF-B family of transcription factors. Here we show that mammary glands of Trcp1/ female mice display a hypoplastic phenotype, whereas no effects on cell proliferation are observed in other somatic cells. To investigate further the role of Trcp1 in mammary gland development, we generated transgenic mice expressing human Trcp1 targeted to epithelial cells under the control of the mouse mammary tumor virus (MMTV) long terminal repeat promoter. Compared to controls, MMTV Trcp1 mammary glands display an increase in lateral ductal branching and extensive arrays of alveolus-like protuberances. The mammary epithelia of MMTV Trcp1 mice proliferate more and show increased NF-B DNA binding activity and higher levels of nuclear NF-B p65/RelA. In addition, 38% of transgenic mice develop tumors, including mammary, ovarian, and uterine carcinomas. The targeting of Trcp1 to lymphoid organs produces no effects on these tissues. In summary, our results support the notion that Trcp1 positively controls the proliferation of breast epithelium and indicate that alteration of Trcp1 function and expression may contribute to malignant behavior of breast tumors, at least in part through NF-B transactivation.