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Nucleophosmin/B23 is a negative regulator of estrogen receptor α expression via AP2γ in endometrial cancer cells

Chiao-Yun Lin1,2, Angel Chao1,2,3, Tzu-Hao Wang1,2,3

  • 1Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Taoyuan, Taiwan.

Oncotarget
|August 17, 2016
PubMed

Insights

Nucleophosmin (B23) and activator protein-2γ (AP2γ) suppress estrogen receptor α (ERα) in endometrial cancer. Inhibiting B23 or AP2γ restores ERα expression, potentially sensitizing hormone-refractory cancers to endocrine therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Endocrinology

Background:

  • Endometrial cancers often lose estrogen and progesterone receptor expression during recurrence, limiting hormonal therapy effectiveness.
  • Restoring steroid hormone receptor expression is crucial for improving endocrine therapy outcomes in recurrent endometrial cancer.

Purpose of the Study:

  • To investigate the role of nucleophosmin (NPM1/B23) and activator protein-2γ (TFAP2C/AP2γ) in regulating estrogen receptor α (ESR1/ERα) expression in endometrial cancer.
  • To explore the potential of targeting B23 or AP2γ to restore ERα expression and sensitize hormone-refractory endometrial cancers to therapy.

Main Methods:

  • Investigated the effect of B23 suppression on ERα expression in endometrial cancer cells.
  • Examined the mechanism of ERα transcriptional regulation by the B23 and AP2γ complex.
  • Utilized knockdown strategies (B23 or AP2γ) in cell lines and a xenograft model.
  • Assessed ERα-regulated gene expression and response to megesterol acetate.
  • Correlated AP2γ immunohistochemical expression with patient prognosis.

Main Results:

  • Nucleophosmin (B23) suppression restored estrogen receptor α (ERα) expression in endometrial cancer cells.
  • B23 and activator protein-2γ (AP2γ) form a complex that transcriptionally represses ERα.
  • Knockdown of B23 or AP2γ reactivated ERα and its downstream target genes.
  • AP2γ knockdown sensitized endometrial cancer xenografts to megesterol acetate via ERα upregulation.
  • Increased AP2γ expression correlated with an adverse prognosis in endometrial cancer patients.

Conclusions:

  • B23 and AP2γ cooperatively suppress ERα expression in endometrial cancer.
  • Targeting B23 or AP2γ presents a potential therapeutic strategy to restore ERα expression and overcome endocrine resistance in endometrial cancer.
Keywords:
activator protein-2γendometrial cancerestrogen receptor αhormonal therapynucleophosmin

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