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Keap1 mutations and Nrf2 pathway activation in epithelial ovarian cancer

Panagiotis A Konstantinopoulos1, Dimitrios Spentzos, Elena Fountzilas

  • 1Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. pkonstan@bidmc.harvard.edu

Cancer Research
|June 17, 2011
PubMed

Insights

The Keap1-Nrf2 pathway, often activated in epithelial ovarian cancer (EOC), is linked to platinum resistance. Mutations in Keap1 and Nrf2 pathway activation correlate with poorer outcomes in EOC patients receiving chemotherapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Epithelial ovarian cancer (EOC) frequently develops resistance to platinum-based chemotherapy.
  • The Keap1-Nrf2 pathway regulates cellular responses to electrophilic stress, including platinum compounds used in chemotherapy.

Purpose of the Study:

  • To investigate the role of Kelch-like ECH-associated protein 1 (Keap1) mutations and NF-E2-related factor 2 (Nrf2) pathway activation in EOC.
  • To correlate these molecular alterations with platinum resistance and patient clinical outcomes.

Main Methods:

  • Nrf2 immunohistochemistry and quantitative real-time PCR to assess pathway activation and Nrf2 target gene expression.
  • Keap1 sequencing to identify mutations.
  • In vitro studies using RNAi-mediated knockdown of Keap1.
  • Microarray analysis of EOC subtypes.

Main Results:

  • Nrf2 pathway activation (nuclear localization) was observed in over half of EOC specimens, particularly in clear cell subtypes.
  • Keap1 mutations were identified in 29% of clear cell and 8% of non-clear cell EOC samples.
  • Nrf2 pathway activation and Keap1 knockdown correlated with carboplatin resistance in vitro.
  • Patients with Nrf2 pathway activation showed reduced complete response rates, increased platinum resistance, and shorter overall survival.

Conclusions:

  • Keap1 mutations are present in EOC.
  • The Keap1-Nrf2 pathway plays a significant role in mediating chemoresistance in EOC.
  • Nrf2 pathway activation serves as a potential biomarker for platinum resistance and poor prognosis in EOC.

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