Genome co-amplification upregulates a mitotic gene network activity that predicts outcome and response to mitotic protein inhibitors in breast cancer

Zhi Hu, Jian Hua Mao, Christina Curtis, Ge Huang, Shenda Gu, Laura Heiser, Marc E. Lenburg, James Korkola, Nora Bayani, Shamith Samarajiwa, Jose A. Seoane, Mark Dane, Amanda Esch, Heidi Feiler, Nicholas J. Wang, Mary Ann Hardwicke, Sylvie Laquerre, Jeff Jackson, Kenneth Wood, Barbara WeberPaul Spellman, Samuel Aparicio, Richard Wooster, Carlos Caldas, Joe Gray

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Background: High mitotic activity is associated with the genesis and progression of many cancers. Small molecule inhibitors of mitotic apparatus proteins are now being developed and evaluated clinically as anticancer agents. With clinical trials of several of these experimental compounds underway, it is important to understand the molecular mechanisms that determine high mitotic activity, identify tumor subtypes that carry molecular aberrations that confer high mitotic activity, and to develop molecular markers that distinguish which tumors will be most responsive to mitotic apparatus inhibitors. Methods: We identified a coordinately regulated mitotic apparatus network by analyzing gene expression profiles for 53 malignant and non-malignant human breast cancer cell lines and two separate primary breast tumor datasets. We defined the mitotic network activity index (MNAI) as the sum of the transcriptional levels of the 54 coordinately regulated mitotic apparatus genes. The effect of those genes on cell growth was evaluated by small interfering RNA (siRNA). Results: High MNAI was enriched in basal-like breast tumors and was associated with reduced survival duration and preferential sensitivity to inhibitors of the mitotic apparatus proteins, polo-like kinase, centromere associated protein E and aurora kinase designated GSK462364, GSK923295 and GSK1070916, respectively. Co-amplification of regions of chromosomes 8q24, 10p15-p12, 12p13, and 17q24-q25 was associated with the transcriptional upregulation of this network of 54 mitotic apparatus genes, and we identify transcription factors that localize to these regions and putatively regulate mitotic activity. Knockdown of the mitotic network by siRNA identified 22 genes that might be considered as additional therapeutic targets for this clinically relevant patient subgroup. Conclusions: We define a molecular signature which may guide therapeutic approaches for tumors with high mitotic network activity.

Original languageEnglish (US)
Article number70
JournalBreast Cancer Research
Volume18
Issue number1
DOIs
StatePublished - Jul 1 2016

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Spindle Apparatus
Gene Regulatory Networks
Up-Regulation
Genome
Breast Neoplasms
Proteins
Small Interfering RNA
Genes
Neoplasms
Aurora Kinases
Transcriptome
Antineoplastic Agents
Protein Kinases
Transcription Factors
Phosphotransferases
Chromosomes
Clinical Trials
Cell Line
Survival
Therapeutics

Keywords

  • Breast cancer
  • Mitotic index
  • Novel therapeutics
  • Predictive biomarker

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Genome co-amplification upregulates a mitotic gene network activity that predicts outcome and response to mitotic protein inhibitors in breast cancer. / Hu, Zhi; Mao, Jian Hua; Curtis, Christina; Huang, Ge; Gu, Shenda; Heiser, Laura; Lenburg, Marc E.; Korkola, James; Bayani, Nora; Samarajiwa, Shamith; Seoane, Jose A.; Dane, Mark; Esch, Amanda; Feiler, Heidi; Wang, Nicholas J.; Hardwicke, Mary Ann; Laquerre, Sylvie; Jackson, Jeff; Wood, Kenneth; Weber, Barbara; Spellman, Paul; Aparicio, Samuel; Wooster, Richard; Caldas, Carlos; Gray, Joe.

In: Breast Cancer Research, Vol. 18, No. 1, 70, 01.07.2016.

Research output: Contribution to journalArticle

Hu, Z, Mao, JH, Curtis, C, Huang, G, Gu, S, Heiser, L, Lenburg, ME, Korkola, J, Bayani, N, Samarajiwa, S, Seoane, JA, Dane, M, Esch, A, Feiler, H, Wang, NJ, Hardwicke, MA, Laquerre, S, Jackson, J, Wood, K, Weber, B, Spellman, P, Aparicio, S, Wooster, R, Caldas, C & Gray, J 2016, 'Genome co-amplification upregulates a mitotic gene network activity that predicts outcome and response to mitotic protein inhibitors in breast cancer', Breast Cancer Research, vol. 18, no. 1, 70. https://doi.org/10.1186/s13058-016-0728-y
Hu, Zhi ; Mao, Jian Hua ; Curtis, Christina ; Huang, Ge ; Gu, Shenda ; Heiser, Laura ; Lenburg, Marc E. ; Korkola, James ; Bayani, Nora ; Samarajiwa, Shamith ; Seoane, Jose A. ; Dane, Mark ; Esch, Amanda ; Feiler, Heidi ; Wang, Nicholas J. ; Hardwicke, Mary Ann ; Laquerre, Sylvie ; Jackson, Jeff ; Wood, Kenneth ; Weber, Barbara ; Spellman, Paul ; Aparicio, Samuel ; Wooster, Richard ; Caldas, Carlos ; Gray, Joe. / Genome co-amplification upregulates a mitotic gene network activity that predicts outcome and response to mitotic protein inhibitors in breast cancer. In: Breast Cancer Research. 2016 ; Vol. 18, No. 1.
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abstract = "Background: High mitotic activity is associated with the genesis and progression of many cancers. Small molecule inhibitors of mitotic apparatus proteins are now being developed and evaluated clinically as anticancer agents. With clinical trials of several of these experimental compounds underway, it is important to understand the molecular mechanisms that determine high mitotic activity, identify tumor subtypes that carry molecular aberrations that confer high mitotic activity, and to develop molecular markers that distinguish which tumors will be most responsive to mitotic apparatus inhibitors. Methods: We identified a coordinately regulated mitotic apparatus network by analyzing gene expression profiles for 53 malignant and non-malignant human breast cancer cell lines and two separate primary breast tumor datasets. We defined the mitotic network activity index (MNAI) as the sum of the transcriptional levels of the 54 coordinately regulated mitotic apparatus genes. The effect of those genes on cell growth was evaluated by small interfering RNA (siRNA). Results: High MNAI was enriched in basal-like breast tumors and was associated with reduced survival duration and preferential sensitivity to inhibitors of the mitotic apparatus proteins, polo-like kinase, centromere associated protein E and aurora kinase designated GSK462364, GSK923295 and GSK1070916, respectively. Co-amplification of regions of chromosomes 8q24, 10p15-p12, 12p13, and 17q24-q25 was associated with the transcriptional upregulation of this network of 54 mitotic apparatus genes, and we identify transcription factors that localize to these regions and putatively regulate mitotic activity. Knockdown of the mitotic network by siRNA identified 22 genes that might be considered as additional therapeutic targets for this clinically relevant patient subgroup. Conclusions: We define a molecular signature which may guide therapeutic approaches for tumors with high mitotic network activity.",
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T1 - Genome co-amplification upregulates a mitotic gene network activity that predicts outcome and response to mitotic protein inhibitors in breast cancer

AU - Hu, Zhi

AU - Mao, Jian Hua

AU - Curtis, Christina

AU - Huang, Ge

AU - Gu, Shenda

AU - Heiser, Laura

AU - Lenburg, Marc E.

AU - Korkola, James

AU - Bayani, Nora

AU - Samarajiwa, Shamith

AU - Seoane, Jose A.

AU - Dane, Mark

AU - Esch, Amanda

AU - Feiler, Heidi

AU - Wang, Nicholas J.

AU - Hardwicke, Mary Ann

AU - Laquerre, Sylvie

AU - Jackson, Jeff

AU - Wood, Kenneth

AU - Weber, Barbara

AU - Spellman, Paul

AU - Aparicio, Samuel

AU - Wooster, Richard

AU - Caldas, Carlos

AU - Gray, Joe

PY - 2016/7/1

Y1 - 2016/7/1

N2 - Background: High mitotic activity is associated with the genesis and progression of many cancers. Small molecule inhibitors of mitotic apparatus proteins are now being developed and evaluated clinically as anticancer agents. With clinical trials of several of these experimental compounds underway, it is important to understand the molecular mechanisms that determine high mitotic activity, identify tumor subtypes that carry molecular aberrations that confer high mitotic activity, and to develop molecular markers that distinguish which tumors will be most responsive to mitotic apparatus inhibitors. Methods: We identified a coordinately regulated mitotic apparatus network by analyzing gene expression profiles for 53 malignant and non-malignant human breast cancer cell lines and two separate primary breast tumor datasets. We defined the mitotic network activity index (MNAI) as the sum of the transcriptional levels of the 54 coordinately regulated mitotic apparatus genes. The effect of those genes on cell growth was evaluated by small interfering RNA (siRNA). Results: High MNAI was enriched in basal-like breast tumors and was associated with reduced survival duration and preferential sensitivity to inhibitors of the mitotic apparatus proteins, polo-like kinase, centromere associated protein E and aurora kinase designated GSK462364, GSK923295 and GSK1070916, respectively. Co-amplification of regions of chromosomes 8q24, 10p15-p12, 12p13, and 17q24-q25 was associated with the transcriptional upregulation of this network of 54 mitotic apparatus genes, and we identify transcription factors that localize to these regions and putatively regulate mitotic activity. Knockdown of the mitotic network by siRNA identified 22 genes that might be considered as additional therapeutic targets for this clinically relevant patient subgroup. Conclusions: We define a molecular signature which may guide therapeutic approaches for tumors with high mitotic network activity.

AB - Background: High mitotic activity is associated with the genesis and progression of many cancers. Small molecule inhibitors of mitotic apparatus proteins are now being developed and evaluated clinically as anticancer agents. With clinical trials of several of these experimental compounds underway, it is important to understand the molecular mechanisms that determine high mitotic activity, identify tumor subtypes that carry molecular aberrations that confer high mitotic activity, and to develop molecular markers that distinguish which tumors will be most responsive to mitotic apparatus inhibitors. Methods: We identified a coordinately regulated mitotic apparatus network by analyzing gene expression profiles for 53 malignant and non-malignant human breast cancer cell lines and two separate primary breast tumor datasets. We defined the mitotic network activity index (MNAI) as the sum of the transcriptional levels of the 54 coordinately regulated mitotic apparatus genes. The effect of those genes on cell growth was evaluated by small interfering RNA (siRNA). Results: High MNAI was enriched in basal-like breast tumors and was associated with reduced survival duration and preferential sensitivity to inhibitors of the mitotic apparatus proteins, polo-like kinase, centromere associated protein E and aurora kinase designated GSK462364, GSK923295 and GSK1070916, respectively. Co-amplification of regions of chromosomes 8q24, 10p15-p12, 12p13, and 17q24-q25 was associated with the transcriptional upregulation of this network of 54 mitotic apparatus genes, and we identify transcription factors that localize to these regions and putatively regulate mitotic activity. Knockdown of the mitotic network by siRNA identified 22 genes that might be considered as additional therapeutic targets for this clinically relevant patient subgroup. Conclusions: We define a molecular signature which may guide therapeutic approaches for tumors with high mitotic network activity.

KW - Breast cancer

KW - Mitotic index

KW - Novel therapeutics

KW - Predictive biomarker

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