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Estrogen regulates tumor growth through a nonclassical pathway that includes the transcription factors ERβ and KLF5

Yuka Nakajima1, Kensuke Akaogi, Takashi Suzuki

  • 1Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan.

Science Signaling
|April 14, 2011
PubMed

Insights

Antiestrogens and estrogens impact prostate cancer growth by regulating estrogen receptor β (ERβ) and Krüppel-like factor 5 (KLF5). This ERβ-KLF5 pathway influences prostate cancer cell anoikis and tumor suppression.

Area of Science:

  • Molecular Endocrinology
  • Cancer Biology
  • Prostate Cancer Research

Background:

  • Antiestrogens show promise in inhibiting androgen-insensitive prostate cancer.
  • Estrogen receptor β (ERβ) plays a role in cellular responses to hormones.
  • Krüppel-like factor 5 (KLF5) is a transcription factor implicated in tumor suppression.

Purpose of the Study:

  • To elucidate the mechanism by which antiestrogens and estrogens regulate prostate cancer growth via ERβ.
  • To investigate the interaction between ERβ, KLF5, and downstream targets in prostate cancer.
  • To determine the clinical relevance of ERβ and KLF5 expression in prostate cancer patients.

Main Methods:

  • Investigated the role of ERβ in mediating antiestrogen effects using ICI 182,780 (ICI).
  • Analyzed the association of ERβ with gene promoters via KLF5.
  • Examined the recruitment of CREB-binding protein (CBP) and WW domain containing E3 ubiquitin protein ligase 1 (WWP1) under different hormonal conditions.
  • Assessed FOXO1 transcription and prostate cancer cell anoikis.
  • Correlated KLF5 and ERβ expression with patient survival data.

Main Results:

  • ICI treatment enhanced ERβ and KLF5 recruitment to the FOXO1 promoter, increasing FOXO1 transcription and inducing anoikis, thus suppressing tumor growth.
  • Estrogen promoted the formation of ERβ, KLF5, and WWP1 complexes, leading to KLF5 ubiquitination and degradation.
  • Combined expression of KLF5 and ERβ correlated with improved cancer-specific survival in prostate cancer patients.

Conclusions:

  • Estrogen receptor β (ERβ) mediates the effects of antiestrogens and estrogens on prostate cancer.
  • The ERβ-KLF5 pathway regulates prostate cancer cell fate through FOXO1 transcription and anoikis.
  • KLF5 and ERβ are potential biomarkers for predicting patient outcomes in prostate cancer.

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