Abstract
Estrogen-related receptor (ERR)α presents structural similarities with estrogen receptor (ER)α. However, it is an orphan receptor not binding to naturally occurring estrogens. This study was designed to investigate the role of ERRα in endometrial cancer progression. Immunohistochemistry analysis on 50 specimens from patients with endometrial cancer showed that ERRα was expressed in all examined tissues and the elevated expression levels of ERRα were associated with advanced clinical stages and serous histological type (p < 0.01 for each). ERRα knockdown with siRNA suppressed angiogenesis via VEGF and cell proliferation in vitro (p < 0.01). Cell cycle and apoptosis assays using flow cytometry and western blot revealed that ERRα knockdown induced cell cycle arrest during the mitotic phase followed by apoptosis initiated by caspase-3. Additionally, ERRα knockdown sensitized cells to paclitaxel. A significant reduction of tumor growth and angiogenesis was also observed in ERRα knockdown xenografts (p < 0.01). These findings indicate that ERRα may serve as a novel molecular target for the treatment of endometrial cancer.
Highlights
Endometrial cancer is the fourth most common malignancy among women [1]
We demonstrated for the first time that silencing ERRα could inhibit the proliferation of uterine endometrial cancer cells in vitro and slow tumor growth in vivo in a mouse xenograft model
We demonstrated that ERRα was highly expressed in the aggressive malignant phenotype and associated with unfavorable clinical outcomes for patients with uterine endometrial cancer
Summary
Endometrial cancer is the fourth most common malignancy among women [1]. In 2012, 53,630 new cases and 8,590 deaths due to endometrial cancer were reported in the United States [2]. The incidence has doubled in the last decade, especially in Japan. Most cases diagnosed at an early stage and lower histological grade can be cured. The prognosis of patients with higher histological grade and invasion beyond the uterus is poor [3]. Other therapeutic modalities such as chemotherapy and radiation therapy are not well-established since the tumor is less sensitive to these [4]. Novel treatment strategies for endometrial cancer are desired
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