MYC pathway activation in triple-negative breast cancer is synthetic lethal with CDK inhibition

被引：275

作者：

Horiuchi, Dai ^{[1
]}

Kusdra, Leonard ^{[1
]}

Huskey, Noelle E. ^{[1
]}

Chandriani, Sanjay ^{[2
,3
]}

Lenburg, Marc E. ^{[7
]}

Gonzalez-Angulo, Ana Maria ^{[8
]}

Creasman, Katelyn J. ^{[1
]}

Bazarov, Alexey V. ^{[1
,9
]}

Smyth, James W. ^{[5
]}

Davis, Sarah E. ^{[4
,6
]}

Yaswen, Paul ^{[9
]}

Mills, Gordon B. ^{[8
]}

Esserman, Laura J. ^{[4
,6
]}

Goga, Andrei ^{[1
,6
]}

机构：

[1] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA

[2] Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA 94143 USA

[3] Univ Calif San Francisco, George Williams Hooper Fdn, San Francisco, CA 94143 USA

[4] Univ Calif San Francisco, Dept Surg, San Francisco, CA 94143 USA

[5] Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA

[6] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA

[7] Boston Univ, Sch Med, Dept Med, Sect Computat Biomed, Boston, MA 02118 USA

[8] Univ Texas MD Anderson Canc Ctr, Dept Breast Med Oncol & Syst Biol, Houston, TX 77030 USA

[9] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Div Life Sci, Berkeley, CA 94720 USA

来源：

JOURNAL OF EXPERIMENTAL MEDICINE | 2012年 / 209卷 / 04期

关键词：

GENE-EXPRESSION SIGNATURE; C-MYC; TRANSCRIPTIONAL ACTIVATION; BCL-2; FAMILY; PHOSPHORYLATION; BASAL; APOPTOSIS; SURVIVAL; TUMORS; BIM;

D O I：

10.1084/jem.20111512

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Estrogen, progesterone, and HER2 receptor-negative triple-negative breast cancers encompass the most clinically challenging subtype for which targeted therapeutics are lacking. We find that triple-negative tumors exhibit elevated MYC expression, as well as altered expression of MYC regulatory genes, resulting in increased activity of the MYC pathway. In primary breast tumors, MYC signaling did not predict response to neoadjuvant chemotherapy but was associated with poor prognosis. We exploit the increased MYC expression found in triple-negative breast cancers by using a synthetic-lethal approach dependent on cyclin-dependent kinase (CDK) inhibition. CDK inhibition effectively induced tumor regression in triple-negative tumor xenografts. The proapoptotic BCL-2 family member BIM is up-regulated after CDK inhibition and contributes to this synthetic-lethal mechanism. These results indicate that aggressive breast tumors with elevated MYC are uniquely sensitive to CDK inhibitors.

引用

页码：679 / 696

页数：18

共 78 条

[1] Meta-Analysis and Gene Set Enrichment Relative to ER Status Reveal Elevated Activity of MYC and E2F in the "Basal" Breast Cancer Subgroup [J].

Alles, M. Chehani ;

Gardiner-Garden, Margaret ;

Nott, David J. ;

Wang, Yixin ;

Foekens, John A. ;

Sutherland, Robert L. ;

Musgrove, Elizabeth A. ;

Ormandy, Christopher J. .

PLOS ONE, 2009, 4 (03)

[2] I-SPY 2: An Adaptive Breast Cancer Trial Design in the Setting of Neoadjuvant Chemotherapy [J].

Barker, A. D. ;

Sigman, C. C. ;

Kelloff, G. J. ;

Hylton, N. M. ;

Berry, D. A. ;

Esserman, L. J. .

CLINICAL PHARMACOLOGY & THERAPEUTICS, 2009, 86 (01) :97-100

[3] Descriptive analysis of estrogen receptor (ER)negative, progesterone receptor (PR)-negative, and HER2-negative invasive breast cancer, the so-called triple-negative phenotype - A population-based study from the California Cancer Registry [J].

Bauer, Katrina R. ;

Brown, Monica ;

Cress, Rosemary D. ;

Parise, Carol A. ;

Caggiano, Vincent .

CANCER, 2007, 109 (09) :1721-1728

[4] An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors [J].

Ben-Porath, Ittai ;

Thomson, Matthew W. ;

Carey, Vincent J. ;

Ge, Ruping ;

Bell, George W. ;

Regev, Aviv ;

Weinberg, Robert A. .

NATURE GENETICS, 2008, 40 (05) :499-507

[5] How basal are triple-negative breast cancers? [J].

Bertucci, Francois ;

Finetti, Pascal ;

Cervera, Nathalie ;

Esterni, Benjamin ;

Hermitte, Fabienne ;

Viens, Patrice ;

Birnbaum, Daniel .

INTERNATIONAL JOURNAL OF CANCER, 2008, 123 (01) :236-240

[6] ONCOGENE PROTEIN COEXPRESSION - VALUE OF HA-RAS, C-MYC, C-FOS, AND P53 AS PROGNOSTIC DISCRIMINANTS FOR BREAST-CARCINOMA [J].

BLAND, KI ;

KONSTADOULAKIS, MM ;

VEZERIDIS, MP ;

WANEBO, HJ .

ANNALS OF SURGERY, 1995, 221 (06) :706-720

[7] Covalent capture of kinase-specific phosphopeptides reveals Cdk1-cyclin B substrates [J].

Blethrow, Justin D. ;

Glavy, Joseph S. ;

Morgan, David O. ;

Shokat, Kevan M. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2008, 105 (05) :1442-1447

[8] The triple negative paradox: Primary tumor chemosensitivity of breast cancer subtypes [J].

Carey, Lisa A. ;

Dees, E. Claire ;

Sawyer, Lynda ;

Gatti, Lisa ;

Moore, Dominic T. ;

Collichio, Frances ;

Ollila, David W. ;

Sartor, Carolyn I. ;

Graham, Mark L. ;

Perou, Charles M. .

CLINICAL CANCER RESEARCH, 2007, 13 (08) :2329-2334

[9] Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study [J].

Carey, Lisa A. ;

Perou, Charles M. ;

Livasy, Chad A. ;

Dressler, Lynn G. ;

Cowan, David ;

Conway, Kathleen ;

Karaca, Gamze ;

Troester, Melissa A. ;

Tse, Chiu Kit ;

Edmiston, Sharon ;

Deming, Sandra L. ;

Geradts, Joseph ;

Cheang, Maggie C. U. ;

Nielsen, Torsten O. ;

Moorman, Patricia G. ;

Earp, H. Shelton ;

Millikan, Robert C. .

JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 2006, 295 (21) :2492-2502

[10] A Core MYC Gene Expression Signature Is Prominent in Basal-Like Breast Cancer but Only Partially Overlaps the Core Serum Response [J].

Chandriani, Sanjay ;

Frengen, Eirik ;

Cowling, Victoria H. ;

Pendergrass, Sarah A. ;

Perou, Charles M. ;

Whitfield, Michael L. ;

Cole, Michael D. .

PLOS ONE, 2009, 4 (08)

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