title: Suppression of breast cancer cell growth by Her2-reduced AR serine 81 phosphorylation.
abstract: Breast cancer is a hormone-related carcinoma and the most commonly diagnosed malignancy in women. Although Her-2, estrogen receptor (ER), and progesterone receptor (PR) 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 human epidermal growth factor receptor-2 (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 early growth response protein 1 (Egr1), while cell-cycle inhibitor protein p27 was increased. Besides, Heregulin (HRG)-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.
authors.affiliation: Department of Life Sciences, National Chung Hsing University, Taichung 40227, Taiwan, Republic of China.
authors.forename: Pao-Hsuan
authors.initials: PH
authors.lastname: Huang
authors.affiliation: Department of Nuclear Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan, Republic of China.
authors.forename: Hsin-Yi
authors.initials: HY
authors.lastname: Wang
authors.affiliation: Department of Life Sciences, National Chung Hsing University, Taichung 40227, Taiwan, Republic of China.
authors.forename: Chen-Chuan
authors.initials: CC
authors.lastname: Huang
authors.affiliation: Department of Surgery, Chang Bing Show Chwan Memorial Hospital, Changhua 50544, Taiwan, Republic of China.
authors.forename: Yueh-Tsung
authors.initials: YT
authors.lastname: Lee
authors.affiliation: Department of Surgery, Tungs' Taichung MetroHarbor Hospital, Taichung 43304, Taiwan, Republic of China.
authors.forename: Chia-Herng
authors.initials: CH
authors.lastname: Yue
authors.affiliation: Department of Medical Research, Taichung Veterans General Hospital, Taichung 40705, Taiwan, Republic of China.
authors.forename: Mei-Chih
authors.initials: MC
authors.lastname: Chen
authors.affiliation: Department of Life Sciences, National Chung Hsing University, Taichung 40227, Taiwan, Republic of China.|Department of Biotechnology, Asia University, Taichung 41354, Taiwan, Republic of China.|Department of Medical Research, China Medical University Hospital, Taichung 40447, Taiwan, Republic of China.|Agricultural Biotechnology Center, National Chung Hsing University, Taichung 40227, Taiwan, Republic of China.|Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung 40227, Taiwan, Republic of China.
authors.forename: Ho
authors.initials: H
authors.lastname: Lin
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D000077341:Lapatinib; D015741:Metribolone; D058990:Molecular Targeted Therapy; D010766:Phosphorylation; D011799:Quinazolines / Q000627:therapeutic use; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D000077341:Lapatinib; D015741:Metribolone; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D011944:Receptors, Androgen; C508053:ERBB2 protein, human