LEM4 confers tamoxifen resistance to breast cancer cells by activating cyclin D-CDK4/6-Rb and ERα pathway

被引：64

作者：

Gao, Ang ^{[1
]}

Sun, Tonghua ^{[1
]}

Ma, Gui ^{[1
]}

Cao, Jiangran ^{[1
]}

Hu, Qingxia ^{[1
]}

Chen, Ling ^{[2
]}

Wang, Yanxin ^{[3
]}

Wang, Qianying ^{[1
]}

Sun, Jiafu ^{[1
]}

Wu, Rui ^{[1
]}

Wu, Qiao ^{[1
]}

Zhou, Jiaxi ^{[4
,5
,6
]}

Liu, Lin ^{[1
]}

Hu, Junjie ^{[1
,7
]}

Dong, Jin-Tang ^{[1
,8
]}

Zhu, Zhengmao ^{[1
]}

机构：

[1] Nankai Univ, Coll Life Sci, Dept Genet & Cell Biol, Tianjin 300071, Peoples R China

[2] Tianjin Cent Hosp Gynecol & Obstet, Dept Pathol, Tianjin 300100, Peoples R China

[3] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Pharmacol, Singapore, Singapore

[4] Chinese Acad Med Sci, State Key Lab Expt Hematol, Inst Hematol, 288 Nanjing Rd, Tianjin 300020, Peoples R China

[5] Chinese Acad Med Sci, Blood Dis Hosp, 288 Nanjing Rd, Tianjin 300020, Peoples R China

[6] Peking Union Med Coll, 288 Nanjing Rd, Tianjin 300020, Peoples R China

[7] Chinese Acad Sci, CAS Ctr Excellence Biomacromol, Inst Biophys, Natl Lab Biomacromol, Beijing 100101, Peoples R China

[8] Emory Univ, Sch Med, Dept Hematol & Med Oncol, Winship Canc Inst, Atlanta, GA 30322 USA

来源：

NATURE COMMUNICATIONS | 2018年 / 9卷

基金：

中国国家自然科学基金;

关键词：

NUCLEAR-ENVELOPE RUPTURE; ESTROGEN-RECEPTOR-ALPHA; ENDOCRINE RESISTANCE; AURORA-A; EXPRESSION SIGNATURE; MEMBRANE PROTEIN; DNA-DAMAGE; KINASE; CDK4; PALBOCICLIB;

D O I：

10.1038/s41467-018-06309-8

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：17

共 60 条

[31] MAN1, an inner nuclear membrane protein that shares the LEM domain with lamina-associated polypeptide 2 and emerin [J].

Lin, F ;

Blake, DL ;

Callebaut, I ;

Skerjanc, IS ;

Holmer, L ;

McBurney, MW ;

Paulin-Levasseur, M ;

Worman, HJ .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (07) :4840-4847

[32] PIK3CA mutations associated with gene signature of low mTORC1 signaling and better outcomes in estrogen receptor-positive breast cancer [J].

Loi, Sherene ;

Haibe-Kains, Benjamin ;

Majjaj, Samira ;

Lallemand, Francoise ;

Durbecq, Virginie ;

Larsimont, Denis ;

Gonzalez-Angulo, Ana M. ;

Pusztai, Lajos ;

Symmans, W. Fraser ;

Bardelli, Alberto ;

Ellis, Paul ;

Tutt, Andrew N. J. ;

Gillett, Cheryl E. ;

Hennessy, Bryan T. ;

Mills, Gordon B. ;

Phillips, Wayne A. ;

Piccart, Martine J. ;

Speed, Terence P. ;

McArthur, Grant A. ;

Sotiriou, Christos .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2010, 107 (22) :10208-10213

[33] Effects of cyclin D1 gene amplification and protein expression on time to recurrence in postmenopausal breast cancer patients treated with anastrozole or tamoxifen: a TransATAC study [J].

Lundgren, Katja ;

Brown, Matthew ;

Pineda, Silvia ;

Cuzick, Jack ;

Salter, Janine ;

Zabaglo, Lila ;

Howell, Anthony ;

Dowsett, Mitch ;

Landberg, Goeran .

BREAST CANCER RESEARCH, 2012, 14 (02)

[34]

Martin M, 2017, NAT COMMUN, V8, DOI [10.1038/s41467-017-01864-y, 10.1038/ncomms15127]

[35] A phase II neoadjuvant trial of anastrozole, fulvestrant, and gefitinib in patients with newly diagnosed estrogen receptor positive breast cancer [J].

Massarweh, Suleiman ;

Tham, Yee L. ;

Huang, Jian ;

Sexton, Krystal ;

Weiss, Heidi ;

Tsimelzon, Anna ;

Beyer, Amanda ;

Rimawi, Mothaffar ;

Cai, Wei Yen ;

Hilsenbeck, Susan ;

Fuqua, Suzanne ;

Elledge, Richard .

BREAST CANCER RESEARCH AND TREATMENT, 2011, 129 (03) :819-827

[36] HER-2 gene amplification can be acquired as breast cancer progresses [J].

Meng, SD ;

Tripathy, D ;

Shete, S ;

Ashfaq, R ;

Haley, B ;

Perkins, S ;

Beitsch, P ;

Khan, A ;

Euhus, D ;

Osborne, C ;

Frenkel, E ;

Hoover, S ;

Leitch, M ;

Clifford, E ;

Vitetta, E ;

Morrison, L ;

Herlyn, D ;

Terstappen, LWMM ;

Fleming, T ;

Fehm, T ;

Tucker, T ;

Lane, N ;

Wang, JQ ;

Uhr, J .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (25) :9393-9398

[37] An expression signature for p53 status in human breast cancer predicts mutation status, transcriptional effects, and patient survival [J].

Miller, LD ;

Smeds, J ;

George, J ;

Vega, VB ;

Vergara, L ;

Ploner, A ;

Pawitan, Y ;

Hall, P ;

Klaar, S ;

Liu, ET ;

Bergh, J .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2005, 102 (38) :13550-13555

[38] Endocrine resistance in hormone-responsive breast cancer: mechanisms and therapeutic strategies [J].

Murphy, Conleth G. ;

Dickler, Maura N. .

[39] Biological determinants of endocrine resistance in breast cancer [J].

Musgrove, Elizabeth A. ;

Sutherland, Robert L. .

NATURE REVIEWS CANCER, 2009, 9 (09) :631-643

[40] Proteasome-dependent degradation of the human estrogen receptor [J].

Nawaz, Z ;

Lonard, DM ;

Dennis, AP ;

Smith, CL ;

O'Malley, BW .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (05) :1858-1862

← 1 2 3 4 5 6 →