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An Orthotopic Murine Model of Human Prostate Cancer Metastasis
06:48

An Orthotopic Murine Model of Human Prostate Cancer Metastasis

Published on: September 18, 2013

Androgen-dependent regulation of Her-2/neu in prostate cancer cells

Raanan Berger1, Douglas I Lin, Maria Nieto

  • 1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

Cancer Research
|June 3, 2006
PubMed

Insights

Prostate cancer cells overexpressing Her-2/neu survive hormone therapy by activating the androgen receptor (AR). Targeting both Her-2/neu and AR simultaneously induces cell death, offering a new therapeutic strategy for hormone-refractory prostate cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Mechanisms of prostate cancer (PCa) progression to hormone-refractory disease are not fully understood.
  • The role of androgen receptor (AR) and Her-2/neu in PCa survival and treatment resistance requires further investigation.

Purpose of the Study:

  • To investigate the relationship between androgen receptor (AR) and Her-2/neu in prostate cancer cells.
  • To elucidate the role of Her-2/neu in promoting survival and growth in an androgen-deficient environment.
  • To explore the therapeutic potential of targeting Her-2/neu in hormone-refractory prostate cancer.

Main Methods:

  • In vitro studies using LNCaP cells to assess Her-2/neu expression and phosphorylation under varying androgen concentrations and AR blockade.
  • In vivo studies involving orthotopically injected LNCaP cells in mice to evaluate Her-2/neu induction post-castration.
  • Gene knockdown experiments using short hairpin RNA (shRNA) targeting AR and Her-2/neu, individually and simultaneously.

Main Results:

  • Her-2/neu overexpression activates the AR pathway, conferring a survival advantage in androgen-deficient conditions.
  • Androgen deprivation or AR blockade induced Her-2/neu expression and phosphorylation, which decreased with androgen reintroduction.
  • Simultaneous targeting of Her-2/neu and AR resulted in significant cell death, with surviving cells showing low Her-2/neu expression.

Conclusions:

  • Her-2/neu induction and activation in an androgen-depleted environment or via AR inactivation promotes ablation-resistant prostate cancer cell survival.
  • These findings provide a biochemical rationale for targeting Her-2/neu in patients with hormone-refractory prostate cancer.

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