Department of Biology, Yeshiva University, New York, NY, USA.
Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Signal Transduct Target Ther. 2017;2:17035-. doi: 10.1038/sigtrans.2017.35. Epub 2017 Aug 25.
Estrogen-related receptor alpha (ERRα) is an orphan nuclear factor that is a master regulator of cellular energy metabolism. ERRα is overexpressed in a variety of tumors, including ovarian, prostate, colorectal, cervical and breast, and is associated with a more aggressive tumor and a worse outcome. In breast cancer, specifically, high ERRα expression is associated with an increased rate of recurrence and a poor prognosis. Because of the common functions of ERRα and the mTORC1/S6K1 signaling pathway in regulation of cellular metabolism and breast cancer pathogenesis, we focused on investigating the biochemical relationship between ERRα and S6K1. We found that ERRα negatively regulates S6K1 expression by directly binding to its promoter. Downregulation of ERRα expression sensitized ERα-negative breast cancer cells to mTORC1/S6K1 inhibitors. Therefore, our results show that combinatorial inhibition of ERRα and mTORC1/S6K1 may have clinical utility in treatment of triple-negative breast cancer, and warrants further investigation.
雌激素相关受体α（ERRα）是一种孤儿核受体，是细胞能量代谢的主要调节因子。ERRα在多种肿瘤中过度表达，包括卵巢、前列腺、结直肠、宫颈和乳腺，并且与更具侵袭性的肿瘤和更差的预后相关。在乳腺癌中，高 ERRα 表达与更高的复发率和预后不良相关。由于 ERRα 和 mTORC1/S6K1 信号通路在调节细胞代谢和乳腺癌发病机制方面的常见功能，我们专注于研究 ERRα 和 S6K1 之间的生化关系。我们发现 ERRα 通过直接结合其启动子来负调控 S6K1 的表达。下调 ERRα 表达使 ERα 阴性乳腺癌细胞对 mTORC1/S6K1 抑制剂敏感。因此，我们的结果表明，联合抑制 ERRα 和 mTORC1/S6K1 可能在治疗三阴性乳腺癌方面具有临床应用价值，值得进一步研究。
