ARID1A Regulates Progesterone Receptor Expression in Early Endometrial Endometrioid Carcinoma Pathogenesis

Shiho Asaka, Ying Liu, Zheng Cheng Yu, Yohan Suryo Rahmanto, Motoki Ono, Ryoichi Asaka, Tsutomu Miyamoto, Ting Tai Yen, Ayse Ayhan, Tian Li Wang, Ie Ming Shih

Research output: Contribution to journalArticlepeer-review

Abstract

Loss of progesterone receptor (PR) expression is an established risk factor for unresponsiveness to progesterone therapy in patients with endometrial atypical hyperplasia and endometrioid carcinoma. ARID1A is one of the most commonly mutated genes in endometrioid carcinomas, and the loss of its expression is associated with tumor progression. In this study, we investigated the roles of ARID1A deficiency in PR expression in human and murine endometrial epithelial neoplasia. An analysis of genome-wide chromatin immunoprecipitation sequencing in isogenic ARID1A−/− and ARID1A+/+ human endometrial epithelial cells revealed that ARID1A−/− cells showed significantly reduced chromatin immunoprecipitation sequencing signals for ARID1A, BRG1, and H3K27AC in the PgR enhancer region. We then performed immunohistochemistry to correlate the protein expression levels of ARID1A, estrogen receptor, and PR in 50 human samples of endometrial atypical hyperplasia and 75 human samples of endometrial carcinomas. The expression levels of PR but not were significantly lower in ARID1A-deficient low-grade endometrial carcinomas and atypical hyperplasia (P =.0002). When Pten and Pten/Arid1a conditional knockout murine models were used, Pten−/−;Arid1a−/− mice exhibited significantly decreased epithelial PR expression in endometrial carcinomas (P =.003) and atypical hyperplasia (P <.0001) compared with that in the same tissues from Pten−/−;Arid1a+/+ mice. Our data suggest that the loss of ARID1A expression, as occurs in ARID1A-mutated endometrioid carcinomas, decreases PgR transcription by modulating the PgR enhancer region during early tumor development.

Original languageEnglish (US)
Article number100045
JournalModern Pathology
Volume36
Issue number2
DOIs
StatePublished - Feb 2023

Keywords

  • ARID1A
  • atypical hyperplasia
  • endometrial endometrioid carcinoma
  • estrogen receptor
  • knockout mouse
  • progesterone receptor

ASJC Scopus subject areas

  • General Medicine

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