Therapeutic Ligands Antagonize Estrogen Receptor Function by Impairing Its Mobility (Cell. 2019, 178(4):949-963.e18.)

報告日期: 2019/10/25
報告時間: 17:10/18:00
報告學生: 陳昱志
講評老師: 王家義

Therapeutic Ligands Antagonize Estrogen Receptor Function by Impairing Its Mobility

Jane Guan et al., 2019, Cell

Speaker: Yu-Chih Chen                                   Time: 2019/10/25

Commentator: Chia-Yih Wang                              Place: Room 602


Breast cancer is the most frequent cancer among women in the world and is divided into three subtypes: estrogen receptor-positive (ER+), HER2 positive, and triple-negative. Because about 70% of breast cancer patients are ER+, Tamoxifen and fulvestrant, which block ER, are efficient therapies for patients with ER+. However, tamoxifen cannot fully suppress ER transcriptional activity because it inhibits ER through targeting ligand binding domain (LBD), which can also promote activation of N-terminal activation function 1 (AF1) domain [1]. Fulvestrant is a selective ER down-regulator leading to the degradation of ER with exposure constraints [2]. Therefore, the authors wanted to discover other ligands that can degrade ER without exposure constraints. They determined ER degradation, anti-proliferation, and LBD conformation profiles of four clinical candidates GDC-0810, GDC-0927, AZD9496, and GNE-274 and found that among these ligands, GDC-0927 showed the greatest ability on ER inhibition through proteasome pathway. They also found that GDC-0927 displayed transcriptional antagonism and performed anti-tumor activity in vivo. The authors also determined the ER-DNA binding sites and gene accessibility sites and found that these sites are different after the treatment of GDC-0927 or fulvestrant. Nevertheless, they also found that fulvestrant and GDC-0927 could immobilize ER in cytoplasm. Finally, the authors demonstrated that LBD mutation of ER could reverse the drug effect and caused fulvestrant and GDC-0927 failed to immobilize ER in cytoplasm. In conclusion, the authors found that GDC-0927 may be a new drug to treat breast cancer.


[1] Sakamoto, T., et al. Estrogen receptor-mediated effects of tamoxifen on human endometrial cancer cells. Mol. Cell. Endocrinol. 2002. 192, 93–104.

[2] van Kruchten, et al. Measuring residual estrogen receptor availability during fulvestrant therapy in patients with metastatic breast cancer. Cancer Discov. 2015. 5, 72–81.