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

Dai Horiuchi, Leonard Kusdra, Noelle E. Huskey, Sanjay Chandriani, Marc E. Lenburg, Ana Maria Gonzalez-Angulo, Katelyn J. Creasman, Alexey V. Bazarov, James W. Smyth, Sarah E. Davis, Paul Yaswen, Gordon Mills, Laura J. Esserman, Andrei Goga

Research output: Contribution to journalArticle

167 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)679-696
Number of pages18
JournalJournal of Experimental Medicine
Volume209
Issue number4
DOIs
StatePublished - Apr 9 2012
Externally publishedYes

Fingerprint

Triple Negative Breast Neoplasms
Cyclin-Dependent Kinases
Breast Neoplasms
Neoplasms
Progesterone Receptors
Regulator Genes
Heterografts
Estrogens
Drug Therapy
Inhibition (Psychology)

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Horiuchi, D., Kusdra, L., Huskey, N. E., Chandriani, S., Lenburg, M. E., Gonzalez-Angulo, A. M., ... Goga, A. (2012). MYC pathway activation in triple-negative breast cancer is synthetic lethal with CDK inhibition. Journal of Experimental Medicine, 209(4), 679-696. https://doi.org/10.1084/jem.20111512

MYC pathway activation in triple-negative breast cancer is synthetic lethal with CDK inhibition. / Horiuchi, Dai; Kusdra, Leonard; Huskey, Noelle E.; Chandriani, Sanjay; Lenburg, Marc E.; Gonzalez-Angulo, Ana Maria; Creasman, Katelyn J.; Bazarov, Alexey V.; Smyth, James W.; Davis, Sarah E.; Yaswen, Paul; Mills, Gordon; Esserman, Laura J.; Goga, Andrei.

In: Journal of Experimental Medicine, Vol. 209, No. 4, 09.04.2012, p. 679-696.

Research output: Contribution to journalArticle

Horiuchi, D, Kusdra, L, Huskey, NE, Chandriani, S, Lenburg, ME, Gonzalez-Angulo, AM, Creasman, KJ, Bazarov, AV, Smyth, JW, Davis, SE, Yaswen, P, Mills, G, Esserman, LJ & Goga, A 2012, 'MYC pathway activation in triple-negative breast cancer is synthetic lethal with CDK inhibition', Journal of Experimental Medicine, vol. 209, no. 4, pp. 679-696. https://doi.org/10.1084/jem.20111512
Horiuchi D, Kusdra L, Huskey NE, Chandriani S, Lenburg ME, Gonzalez-Angulo AM et al. MYC pathway activation in triple-negative breast cancer is synthetic lethal with CDK inhibition. Journal of Experimental Medicine. 2012 Apr 9;209(4):679-696. https://doi.org/10.1084/jem.20111512
Horiuchi, Dai ; Kusdra, Leonard ; Huskey, Noelle E. ; Chandriani, Sanjay ; Lenburg, Marc E. ; Gonzalez-Angulo, Ana Maria ; Creasman, Katelyn J. ; Bazarov, Alexey V. ; Smyth, James W. ; Davis, Sarah E. ; Yaswen, Paul ; Mills, Gordon ; Esserman, Laura J. ; Goga, Andrei. / MYC pathway activation in triple-negative breast cancer is synthetic lethal with CDK inhibition. In: Journal of Experimental Medicine. 2012 ; Vol. 209, No. 4. pp. 679-696.
@article{cbe8f80c6d4f42d28103e0c4f510b53e,
title = "MYC pathway activation in triple-negative breast cancer is synthetic lethal with CDK inhibition",
abstract = "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.",
author = "Dai Horiuchi and Leonard Kusdra and Huskey, {Noelle E.} and Sanjay Chandriani and Lenburg, {Marc E.} and Gonzalez-Angulo, {Ana Maria} and Creasman, {Katelyn J.} and Bazarov, {Alexey V.} and Smyth, {James W.} and Davis, {Sarah E.} and Paul Yaswen and Gordon Mills and Esserman, {Laura J.} and Andrei Goga",
year = "2012",
month = "4",
day = "9",
doi = "10.1084/jem.20111512",
language = "English (US)",
volume = "209",
pages = "679--696",
journal = "Journal of Experimental Medicine",
issn = "0022-1007",
publisher = "Rockefeller University Press",
number = "4",

}

TY - JOUR

T1 - MYC pathway activation in triple-negative breast cancer is synthetic lethal with CDK inhibition

AU - Horiuchi, Dai

AU - Kusdra, Leonard

AU - Huskey, Noelle E.

AU - Chandriani, Sanjay

AU - Lenburg, Marc E.

AU - Gonzalez-Angulo, Ana Maria

AU - Creasman, Katelyn J.

AU - Bazarov, Alexey V.

AU - Smyth, James W.

AU - Davis, Sarah E.

AU - Yaswen, Paul

AU - Mills, Gordon

AU - Esserman, Laura J.

AU - Goga, Andrei

PY - 2012/4/9

Y1 - 2012/4/9

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84861735363&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84861735363&partnerID=8YFLogxK

U2 - 10.1084/jem.20111512

DO - 10.1084/jem.20111512

M3 - Article

VL - 209

SP - 679

EP - 696

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

SN - 0022-1007

IS - 4

ER -