Nucleophosmin/B23 is a negative regulator of estrogen receptor β expression via AP2η in endometrial cancer cells

Endometrial cancers expressing estrogen and progesterone receptors respond to hormonal therapy. The disappearance of steroid hormone receptor expression is common in patients with recurrent disease, ultimately hampering the clinical utility of hormonal therapy. Here, we demonstrate for the first time that nucleophosmin (NPM1/ B23) suppression can restore the expression of estrogen receptor a (ESR1/ERβ) in endometrial cancer cells. Mechanistically, B23 and activator protein-2g (TFAP2C/AP2η) form a complex that acts as a transcriptional repressor of ERβ. Our results indicate that B23 or AP2η knockdown can restore ERβ levels and activate ERβ-regulated genes (e.g., cathepsin D, EBAG9, and TFF1/pS2). Moreover, AP2η knockdown in a xenograft model sensitizes endometrial cancer cells to megesterol acetate through the upregulation of ERβ expression. An increased immunohistochemical expression of AP2η is an adverse prognostic factor in endometrial cancer. In summary, B23 and AP2η may act in combination to suppress ERβ expression in endometrial cancer cells. The inhibition of B23 or AP2η can restore ERβ expression and can serve as a potential strategy for sensitizing hormone-refractory endometrial cancers to endocrine therapy.