期刊
NATURE COMMUNICATIONS
卷 9, 期 -, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-018-06309-8
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资金
- National Natural Science Foundation of China [91649107, 81402320]
- Natural Science Foundation of Tianjin City of China [17JCYBJC24100, 16JCYBJC27000]
- Strategic Priority Research Program (Pilot study) Biological basis of aging and therapeutic strategies of the Chinese Academy of Sciences [XDPB10]
The elucidation of molecular events that confer tamoxifen resistance to estrogen receptor a (ER) positive breast cancer is of major scientific and therapeutic importance. Here, we report that LEM4 overexpression renders ER+ breast cancer cells resistant to tamoxifen by activating the cyclin D-CDK4/6 axis and the ER alpha signaling. We show that LEM4 overexpression accelerates tumor growth. Interaction with LEM4 stabilizes CDK4 and Rb, promotes Rb phosphorylation and the G1/S phase transition. LEM4 depletion or combined tamoxifen and PD0332991 treatment significantly reverses tamoxifen resistance. Furthermore, LEM4 interacts with and stabilizes both Aurora-A and ER alpha, promotes Aurora-A mediated phosphorylation of ER alpha-Ser167, leading to increase in ER alpha DNA-binding and transactivation activity. Elevated levels of LEM4 correlates with poorer relapse-free survival in patients with ER+ breast cancer undergoing endocrine therapy. Thus, LEM4 represents a prognostic marker and an attractive target for breast cancer therapeutics. Functional antagonism of LEM4 could overcome tamoxifen resistance.
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