Integrative analysis of cyclin protein levels identifies cyclin B1 as a classifier and predictor of outcomes in breast cancer

Roshan Agarwal, Ana Maria Gonzalez-Angulo, Simen Myhre, Mark Carey, Ju Seog Lee, Jens Overgaard, Jan Alsner, Katherine Stemke-Hale, Ana Lluch, Richard M. Neve, Wen Lin Kuo, Therese Sorlie, Aysegul Sahin, Vicente Valero, Khandan Keyomarsi, Joe Gray, Anne Lise Borresen-Dale, Gordon Mills, Bryan T. Hennessy

Research output: Contribution to journalArticle

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Abstract

Purpose: We studied the expression levels of cyclins B1, D1, and E1 and the implications of cyclin overexpression for patient outcomes in distinct breast cancer subtypes defined by clinical variables and transcriptional profiling. Experimental Design: The expression levels of cyclins B1, D1, and E1 were quantified in 779 breast tumors and 53 cell lines using reverse phase protein arrays and/or transcriptional profiling. Results: Whereas cyclin E1 overexpression was a specific marker of triple-negative and basal-like tumors, cyclin B1 overexpression occurred in poor prognosis hormone receptor-positive, luminal B and basal-like breast cancers. Cyclin D1 overexpression occurred in luminal and normal-like cancers. Breast cancer subgroups defined by integrated expression of cyclins B1, D1, and E1 correlated significantly (P <0.000001) with tumor subtypes defined by transcriptional profiling and clinical criteria. Across three hormone receptor-positive data sets, cyclin B1 was the dominant cyclin associated with poor prognosis in univariate and multivariate analyses. Although CCNE1 was present in significantly higher copy numbers in basal-like versus other subtypes (ANOVA P <0.001), CCNB1 gene copy number did not show gain in breast cancer. Instead, cyclin B1 expression was increased in tumors with co-occurrence of TP53 mutations and MYC amplification, a combination that seems to characterize basal-like and luminal B tumors. CCNB1 gene expression was significantly correlated with PLK, CENPE, and AURKB gene expression. Conclusion: Cyclins B1, D1, and E1 have distinct expressions in different breast cancer subtypes. Novel PLK, CENPE, and AURKB inhibitors should be assessed for therapeutic utility in poor prognosis cyclin B1-overexpressing breast cancers.

Original languageEnglish (US)
Pages (from-to)3654-3662
Number of pages9
JournalClinical Cancer Research
Volume15
Issue number11
DOIs
StatePublished - Jun 1 2009
Externally publishedYes

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Cyclin B1
Cyclins
Cyclin D1
Breast Neoplasms
Proteins
Neoplasms
Hormones
Gene Expression
Protein Array Analysis
Gene Dosage
Tumor Cell Line
Analysis of Variance
Research Design
Multivariate Analysis
Mutation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Agarwal, R., Gonzalez-Angulo, A. M., Myhre, S., Carey, M., Lee, J. S., Overgaard, J., ... Hennessy, B. T. (2009). Integrative analysis of cyclin protein levels identifies cyclin B1 as a classifier and predictor of outcomes in breast cancer. Clinical Cancer Research, 15(11), 3654-3662. https://doi.org/10.1158/1078-0432.CCR-08-3293

Integrative analysis of cyclin protein levels identifies cyclin B1 as a classifier and predictor of outcomes in breast cancer. / Agarwal, Roshan; Gonzalez-Angulo, Ana Maria; Myhre, Simen; Carey, Mark; Lee, Ju Seog; Overgaard, Jens; Alsner, Jan; Stemke-Hale, Katherine; Lluch, Ana; Neve, Richard M.; Kuo, Wen Lin; Sorlie, Therese; Sahin, Aysegul; Valero, Vicente; Keyomarsi, Khandan; Gray, Joe; Borresen-Dale, Anne Lise; Mills, Gordon; Hennessy, Bryan T.

In: Clinical Cancer Research, Vol. 15, No. 11, 01.06.2009, p. 3654-3662.

Research output: Contribution to journalArticle

Agarwal, R, Gonzalez-Angulo, AM, Myhre, S, Carey, M, Lee, JS, Overgaard, J, Alsner, J, Stemke-Hale, K, Lluch, A, Neve, RM, Kuo, WL, Sorlie, T, Sahin, A, Valero, V, Keyomarsi, K, Gray, J, Borresen-Dale, AL, Mills, G & Hennessy, BT 2009, 'Integrative analysis of cyclin protein levels identifies cyclin B1 as a classifier and predictor of outcomes in breast cancer', Clinical Cancer Research, vol. 15, no. 11, pp. 3654-3662. https://doi.org/10.1158/1078-0432.CCR-08-3293
Agarwal, Roshan ; Gonzalez-Angulo, Ana Maria ; Myhre, Simen ; Carey, Mark ; Lee, Ju Seog ; Overgaard, Jens ; Alsner, Jan ; Stemke-Hale, Katherine ; Lluch, Ana ; Neve, Richard M. ; Kuo, Wen Lin ; Sorlie, Therese ; Sahin, Aysegul ; Valero, Vicente ; Keyomarsi, Khandan ; Gray, Joe ; Borresen-Dale, Anne Lise ; Mills, Gordon ; Hennessy, Bryan T. / Integrative analysis of cyclin protein levels identifies cyclin B1 as a classifier and predictor of outcomes in breast cancer. In: Clinical Cancer Research. 2009 ; Vol. 15, No. 11. pp. 3654-3662.
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AU - Lee, Ju Seog

AU - Overgaard, Jens

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AU - Stemke-Hale, Katherine

AU - Lluch, Ana

AU - Neve, Richard M.

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AU - Sorlie, Therese

AU - Sahin, Aysegul

AU - Valero, Vicente

AU - Keyomarsi, Khandan

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AU - Hennessy, Bryan T.

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