Nucleophosmin/B23 is a negative regulator of estrogen receptor ? expression via AP2? in endometrial cancer cells.

ABSTRACT: 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 ? (ESR1/ER?) in endometrial cancer cells. Mechanistically, B23 and activator protein-2? (TFAP2C/AP2?) form a complex that acts as a transcriptional repressor of ER?. Our results indicate that B23 or AP2? knockdown can restore ER? levels and activate ER?-regulated genes (e.g., cathepsin D, EBAG9, and TFF1/pS2). Moreover, AP2? knockdown in a xenograft model sensitizes endometrial cancer cells to megesterol acetate through the upregulation of ER? expression. An increased immunohistochemical expression of AP2? is an adverse prognostic factor in endometrial cancer. In summary, B23 and AP2? may act in combination to suppress ER? expression in endometrial cancer cells. The inhibition of B23 or AP2? can restore ER? expression and can serve as a potential strategy for sensitizing hormone-refractory endometrial cancers to endocrine therapy.

SUBMITTER: Lin CY 

PROVIDER: S-EPMC5312367 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature