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Inactivation of the candidate tumor suppressor par-4 in endometrial cancer

Gema Moreno-Bueno1, Pablo J Fernandez-Marcos, Manuel Collado

  • 1Breast and Gynecological Cancer Group, Tumor Suppression Group, Spanish National Cancer Center (CNIO), 3 Melchior Fernandez Almagro Street, Madrid E-28029, Spain.

Cancer Research
|March 3, 2007
PubMed

Insights

Prostate apoptosis response 4 (Par-4) acts as a tumor suppressor in human endometrial cancer. Down-regulation and promoter hypermethylation of Par-4 were observed in many endometrial tumors, suggesting its crucial role in preventing cancer development.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Prostate apoptosis response 4 (Par-4) is a proapoptotic protein.
  • Par-4 deficient mice exhibit increased susceptibility to endometrial carcinomas.
  • The role of Par-4 in human endometrial cancer remains to be elucidated.

Purpose of the Study:

  • To investigate the potential of Par-4 as a tumor suppressor gene in human endometrial cancer.
  • To determine the frequency and mechanisms of Par-4 alterations in endometrial carcinomas.

Main Methods:

  • Quantitative reverse transcription-PCR and cDNA arrays were used to assess Par-4 expression levels.
  • Immunohistochemistry was employed to evaluate Par-4 protein status.
  • Mutational analysis and promoter methylation studies were conducted on tumor samples and cell lines.

Main Results:

  • Par-4 down-regulation was detected in approximately 40% of human endometrial carcinomas.
  • Par-4 alterations were more frequent in estrogen receptor-positive tumors and those with microsatellite instability (MSI).
  • Par-4 promoter hypermethylation was identified in 32% of tumors, leading to gene silencing, and was reversible with demethylating agents.

Conclusions:

  • Par-4 functions as a significant tumor suppressor gene in human endometrial carcinogenesis.
  • Down-regulation of Par-4, primarily through promoter hypermethylation, contributes to endometrial tumor development.
  • Restoring Par-4 expression offers a potential therapeutic strategy for endometrial cancer.

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