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

Abstract

Beta-TrCP ubiquitin ligase receptor is required for activation of anti-apoptotic transcription factor NF-kappaB. Beta-TrCP activities are essential for v-Ras- mediated 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-KB-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.

Open PDF

Document Details

Document Type
Technical Report
Publication Date
Jun 01, 2006
Accession Number
ADA484877

Entities

People

  • Vladimir S. Spiegelman

Organizations

  • University of Wisconsin–Madison

Tags

DTIC Thesaurus Topics

  • Apoptosis
  • Biomedical Research
  • Breast Cancer
  • Cell Line
  • Cell Physiological Processes
  • Cells
  • Degradation
  • Inhibition
  • Ionizing Radiation
  • Mammary Glands
  • Neoplasms
  • Proteins
  • Regulations
  • Transcription Factors

Fields of Study

  • Biology

Readers

  • Electrochemical Surface Science
  • Molecular Biology and Genetics
  • Oncology (Cancer Research).