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Brachyury as a potential modulator of androgen receptor activity and a key player in therapy resistance in prostate

Filipe Pinto1,2, Nelma Pértega-Gomes3, José R Vizcaíno4

  • 1Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.

Oncotarget
|April 7, 2016
PubMed

Insights

Brachyury protein promotes resistance to prostate cancer (PCa) therapies like docetaxel. Targeting Brachyury may offer new strategies for treating advanced PCa patients and overcoming treatment resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Prostate cancer (PCa) is a leading cause of cancer death in men.
  • Therapy resistance is a major challenge in managing PCa patients.
  • Brachyury has been identified as a novel biomarker for PCa aggressiveness and poor prognosis.

Purpose of the Study:

  • To investigate the role of Brachyury in the development of therapy resistance in prostate cancer.
  • To determine if Brachyury overexpression affects sensitivity to common chemotherapy drugs.
  • To explore the molecular mechanisms by which Brachyury influences treatment resistance.

Main Methods:

  • Utilized prostate cancer cell lines with manipulated Brachyury expression.
  • Assessed drug resistance to docetaxel and cabazitaxel.
  • Performed Chromatin Immunoprecipitation quantitative PCR (ChiP-qPCR) assays.
  • Evaluated epithelial-to-mesenchymal transition (EMT) and stem cell properties in vitro.
  • Conducted in silico analysis of clinical PCa samples.

Main Results:

  • Brachyury overexpression enhanced resistance to docetaxel and cabazitaxel in PCa cells.
  • Reducing Brachyury levels decreased therapy resistance.
  • Brachyury directly regulates androgen receptor (AR) expression, AMACR, Snail, and Fibronectin.
  • Brachyury promoted EMT and stem cell properties in vitro.
  • Clinical Brachyury-positive PCa samples correlated with aggressiveness and therapy resistance markers (PTEN loss, NEtD markers, ERG, Bcl-2).

Conclusions:

  • Brachyury plays a significant role in promoting chemotherapy resistance in prostate cancer.
  • Brachyury acts as a direct regulator of key pathways involved in PCa progression and resistance.
  • Brachyury represents a promising therapeutic target for advanced prostate cancer patients experiencing treatment resistance.
Keywords:
Brachyuryprostate cancertherapy resistance

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