Role of beta-TrCP Ubiquitin Ligase Receptor in the Development of Breast Cancer

摘要

Beta-TrCP ubiquitin ligase receptor is required for activation of anti-apoptotic transcription factor NF-kappaB. Beta-TrCP activities are essential for v-Rasmediated transformation of cells. As beta-TrCP proteins are pivotal to activation of the NF-kappaB pathway, up-regulation of NF-kappaB transactivation via an increase in beta-TrCP levels and activities may contribute to malignant transformation of cells. Under these conditions, an elevated expression of beta-TrCP is expected to promote cell transformation.Anti-apoptotic effect of NF-kappaB is suggested among the mechanisms implicated in NF-B-driven transformation. NF-kappaB has been shown capable of blocking apoptosis induced by TNFalpha, ionizing radiation, or the chemotherapeutic agents. Inhibition of NF-kappaB activities dramatically potentiates apoptosis of cancer cells induced by various pro-apoptotic stimuli. These and other data indicate that NF-kappaB inhibiting agents could become useful adjuvants in anti-tumor therapies. We hypothesize that beta-TrCP activities are essential for development of breast cancer. To this end we will employ new transgenic mice with inducible dominant negative beta-TrCP2 (dn-bTrCP2) in mammary tissues in breast carcinogenesis model and determine whether inhibition of beta-TrCP function will abrogate development of breast tumors. Since beta-TrCP mediates ubiquitination and degradation of IkappaB in response to IKK-inducing stimuli, identifying the mechanisms of beta-TrCP function in mouse mammary tumors may potentially lead to design of the agents capable of inhibiting beta-TrCP function and effective for cancer prevention and therapy. The result of this study may significantly contribute to our understanding of the development of human breast tumors.