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Project

Defining NRF2 induced tumor invasion in bladder cancer

Funder: Bladder Cancer Advocacy Network

Funding period
USD 50 K
Funding amount
Abstract
Exome sequencing of high grade, muscle-invasive bladder cancer has identified a high rate of activating mutations in NRF2 (Nuclear factor-erythroid derived 2-like 2, Nfe2l2). However, NRF2 has been reported its dual role as tumor suppressor and oncogene, and the role in bladder cancer is still unknown. We have obtained preliminary data that NRF2 mutations were enriched in basal-type bladder cancer and that the bladder cancer cell lines expressing the mutant NRF2 have enhanced invasive phenotype and activated transcriptional pathways involved in cell movement, migration and invasion with elevated expression of osteopontin (SPP1). We therefore hypothesize that NRF2 activating mutations promote invasion and metastasis through increased SPP1 expression in bladder cancer. In this proposal, we will first determine whether NRF2 regulates SPP1 expression and whether increased expression of SPP1 is necessary and sufficient to promote invasion by NRF2 activating mutation in bladder cancer cell lines. Second, we will determine whether NRF2 activation promotes invasion and metastasis in the context of N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced carcinogenesis and progression using a novel Nrf2E79Q conditional knock-in mouse. This in vivo model will allow us to make observations in the context of a normal immune system and tumor microenvironment. Successful completion of this proposal will result in a better understanding of the effects of NRF2 activation on invasion and metastasis, the development of a novel Nrf2 activation mouse model of bladder cancer and provide clues for a novel therapeutic strategy to suppress invasion and metastasis. This will greatly benefit bladder cancer patients.
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System

Categories
  • FOR (ANZSRC)

    1112 Oncology and Carcinogenesis

  • RCDC

    Cancer

  • RCDC

    Genetics

  • RCDC

    Urologic Diseases

  • HRCS HC

    Cancer

  • HRCS RAC

    2.1 Biological and endogenous factors

  • Health Research Areas

    Biomedical

  • Broad Research Areas

    Basic Science