Suppression of Breast Cancer Cell Growth by Her2-Reduced AR Serine 81 Phosphorylation

Pao-Hsuan Huang ； Hsin-Yi Wang ； Chen-Chuan Huang ； Yueh-Tsung Lee ； Chia-Herng Yue ； Mei-Chih Chen ； Ho Lin

《The Chinese Journal of Physiology》 預刊文章 Pp. e1-8

https://doi.org/10.4077/CJP.2016.BAE416

並列摘要

Breast cancer is a hormone-related carcinoma and the most commonly diagnosed malignancy in women. Although Her-2, estrogen receptor, and progesterone receptor are the major diagnostic markers and therapeutic targets to breast cancer, searching for additional molecular targets remains an important issue and one of the candidates is androgen receptor (AR). AR has been shown expressed in 70% breast cancer patients and connects to low recurrence and high survival rate. Our previous study demonstrates that Ser81 phosphorylation of AR in prostate cancer cells is critical for its protein stability modulated by Her2. The aim of this study is to investigate the influence of Her2 and AR in proliferation of breast cancer cell line, MDA-MB-453. The data show that AR which was activated by synthetic androgen R1881 suppressed the proliferation of MDA-MB-453 cells. Notably, AR activation decreased the protein levels of cell growth-related proteins, including cyclin A, cyclin B, and Egr1, while cell-cycle inhibitor protein p27 was increased. Besides, Heregulin-induced Her2 activation decreased the AR protein levels and its Ser81 phosphorylation. Her2 small molecular inhibitor, Lapatinib, dose-dependently suppressed cell proliferation while the levels of phospho-Ser81 AR and p27 protein were increased. Phospho-Ser81 AR was also increased after Her2 knockdown. Specifically, the influence of phospho- Ser81 AR by Lapatinib was primarily found in the nucleus of MDA-MD-453 cells, where the cell proliferation might directly be interfered. In conclusion, our findings indicate that Her2 might negatively regulate AR phosphorylation/activation and contribute to regulate the proliferation of MDA-MB 453 cells.

並列關鍵字

androgen receptor ； breast cancer ； Her ； Lapatinib ； MDA-MB-453 cell line

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