Targeting BCL-2 with the BH3 Mimetic ABT-199 in Estrogen Receptor-Positive Breast Cancer

被引：240

作者：

Vaillant, Francois ^{[1
,6
]}

Merino, Delphine ^{[1
,6
]}

Lee, Lily ^{[1
,6
]}

Breslin, Kelsey ^{[1
]}

Pal, Bhupinder ^{[1
,6
]}

Ritchie, Matthew E. ^{[2
,7
]}

Smyth, Gordon K. ^{[3
,7
]}

Christie, Michael ^{[4
,6
,10
]}

Phillipson, Louisa J. ^{[5
,6
]}

Burns, Christopher J. ^{[5
,6
]}

Mann, G. Bruce ^{[8
]}

Visvader, Jane E. ^{[1
,6
]}

Lindeman, Geoffrey J. ^{[1
,9
,11
,12
,13
]}

机构：

[1] Walter & Eliza Hall Inst Med Res, ACRF Stem Cells & Canc Div, Parkville, Vic 3052, Australia

[2] Walter & Eliza Hall Inst Med Res, Mol Med Div, Parkville, Vic 3052, Australia

[3] Walter & Eliza Hall Inst Med Res, Bioinformat Div, Parkville, Vic 3052, Australia

[4] Walter & Eliza Hall Inst Med Res, Syst Biol & Personalised Med Div, Parkville, Vic 3052, Australia

[5] Walter & Eliza Hall Inst Med Res, Chem Biol Div, Parkville, Vic 3052, Australia

[6] Univ Melbourne, Dept Med Biol, Parkville, Vic 3010, Australia

[7] Univ Melbourne, Dept Math & Stat, Parkville, Vic 3010, Australia

[8] Univ Melbourne, Dept Surg, Parkville, Vic 3010, Australia

[9] Univ Melbourne, Dept Med, Parkville, Vic 3010, Australia

[10] Royal Melbourne Hosp, Dept Anat Pathol, Parkville, Vic 3050, Australia

[11] Royal Melbourne Hosp, Dept Med Oncol, Parkville, Vic 3050, Australia

[12] Royal Melbourne Hosp, Breast Serv, Parkville, Vic 3050, Australia

[13] Royal Womens Hosp, Parkville, Vic 3050, Australia

来源：

CANCER CELL | 2013年 / 24卷 / 01期

基金：

澳大利亚国家健康与医学研究理事会; 英国医学研究理事会;

关键词：

CHRONIC LYMPHOCYTIC-LEUKEMIA; SURVIVAL SIGNALS; CELL-DEATH; THERAPY; FAMILY; INHIBITOR; TUMORS; NAVITOCLAX; ABT-737; ACTIVATION;

D O I：

10.1016/j.ccr.2013.06.002

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

The prosurvival protein BCL-2 is frequently overexpressed in estrogen receptor (ER)-positive breast cancer. We have generated ER-positive primary breast tumor xenografts that recapitulate the primary tumors and demonstrate that the BH3 mimetic ABT-737 markedly improves tumor response to the antiestrogen tamoxifen. Despite abundant BCL-XL expression, similar efficacy was observed with the BCL-2 selective inhibitor ABT-199, revealing that BCL-2 is a crucial target. Unexpectedly, BH3 mimetics were found to counteract the side effect of tamoxifen-induced endometrial hyperplasia. Moreover, BH3 mimetics synergized with phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitors in eliciting apoptosis. Importantly, these two classes of inhibitor further enhanced tumor response in combination therapy with tamoxifen. Collectively, our findings provide a rationale for the clinical evaluation of BH3 mimetics in therapy for breast cancer.

引用

页码：120 / 129

页数：10

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