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

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 i nhibitors 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,more » 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.« less

Authors:
 [1];  [2];  [3];  [1];  [1];  [1];  [4];  [1];  [2];  [5];  [6];  [1];  [1];  [1];  [1];  [7];  [7];  [7];  [8];  [7] more »;  [1];  [9];  [7];  [10];  [1] « less
  1. Oregon Health and Science Univ., Portland, OR (United States)
  2. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
  3. Stanford Univ. of Medicine, CA (United States)
  4. Boston Univ. School of Medicine, MA (United States)
  5. Univ. of Cambridge (United Kingdom)
  6. Stanford Univ. School of Medicine, CA (United States)
  7. GlaxoSmithKline, Philadelphia, PA (United States)
  8. Cytokinetics, Inc., South San Francisco, CA (United States)
  9. BC Cancer Research Center, Vancouver, BC (Canada)
  10. Cambridge Inst. (United Kingdom). Cancer Research UK
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1379500
Grant/Contract Number:
AC02-05CH11231
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Breast Cancer Research
Additional Journal Information:
Journal Volume: 18; Journal Issue: 1; Journal ID: ISSN 1465-542X
Publisher:
BioMed Central
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES

Citation Formats

Hu, Zhi, Mao, Jian-Hua, Curtis, Christina, Huang, Ge, Gu, Shenda, Heiser, Laura, Lenburg, Marc E., Korkola, James E., Bayani, Nora, Samarajiwa, Shamith, Seoane, Jose A., Dane, Mark A., Esch, Amanda, Feiler, Heidi S., Wang, Nicholas J., Hardwicke, Mary Ann, Laquerre, Sylvie, Jackson, Jeff, W. Wood, Kenneth, Weber, Barbara, Spellman, Paul T., Aparicio, Samuel, Wooster, Richard, Caldas, Carlos, and Gray, Joe W. Genome co-amplification upregulates a mitotic gene network activity that predicts outcome and response to mitotic protein inhibitors in breast cancer. United States: N. p., 2016. Web. doi:10.1186/s13058-016-0728-y.
Hu, Zhi, Mao, Jian-Hua, Curtis, Christina, Huang, Ge, Gu, Shenda, Heiser, Laura, Lenburg, Marc E., Korkola, James E., Bayani, Nora, Samarajiwa, Shamith, Seoane, Jose A., Dane, Mark A., Esch, Amanda, Feiler, Heidi S., Wang, Nicholas J., Hardwicke, Mary Ann, Laquerre, Sylvie, Jackson, Jeff, W. Wood, Kenneth, Weber, Barbara, Spellman, Paul T., Aparicio, Samuel, Wooster, Richard, Caldas, Carlos, & Gray, Joe W. Genome co-amplification upregulates a mitotic gene network activity that predicts outcome and response to mitotic protein inhibitors in breast cancer. United States. doi:10.1186/s13058-016-0728-y.
Hu, Zhi, Mao, Jian-Hua, Curtis, Christina, Huang, Ge, Gu, Shenda, Heiser, Laura, Lenburg, Marc E., Korkola, James E., Bayani, Nora, Samarajiwa, Shamith, Seoane, Jose A., Dane, Mark A., Esch, Amanda, Feiler, Heidi S., Wang, Nicholas J., Hardwicke, Mary Ann, Laquerre, Sylvie, Jackson, Jeff, W. Wood, Kenneth, Weber, Barbara, Spellman, Paul T., Aparicio, Samuel, Wooster, Richard, Caldas, Carlos, and Gray, Joe W. 2016. "Genome co-amplification upregulates a mitotic gene network activity that predicts outcome and response to mitotic protein inhibitors in breast cancer". United States. doi:10.1186/s13058-016-0728-y. https://www.osti.gov/servlets/purl/1379500.
@article{osti_1379500,
title = {Genome co-amplification upregulates a mitotic gene network activity that predicts outcome and response to mitotic protein inhibitors in breast cancer},
author = {Hu, Zhi and Mao, Jian-Hua and Curtis, Christina and Huang, Ge and Gu, Shenda and Heiser, Laura and Lenburg, Marc E. and Korkola, James E. and Bayani, Nora and Samarajiwa, Shamith and Seoane, Jose A. and Dane, Mark A. and Esch, Amanda and Feiler, Heidi S. and Wang, Nicholas J. and Hardwicke, Mary Ann and Laquerre, Sylvie and Jackson, Jeff and W. Wood, Kenneth and Weber, Barbara and Spellman, Paul T. and Aparicio, Samuel and Wooster, Richard and Caldas, Carlos and Gray, Joe W.},
abstractNote = {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 i nhibitors 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.},
doi = {10.1186/s13058-016-0728-y},
journal = {Breast Cancer Research},
number = 1,
volume = 18,
place = {United States},
year = 2016,
month = 7
}

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  • To understand how non-malignant human mammary epithelial cells (HMEC) transit from a disorganized proliferating to an organized growth arrested state, and to relate this process to the changes that occur in breast cancer, we studied gene expression changes in non-malignant HMEC grown in three-dimensional cultures, and in a previously published panel of microarray data for 295 breast cancer samples. We hypothesized that the gene expression pattern of organized and growth arrested mammary acini would share similarities with breast tumors with good prognoses. Using Affymetrix HG-U133A microarrays, we analyzed the expression of 22,283 gene transcripts in two HMEC cell lines, 184more » (finite life span) and HMT3522 S1 (immortal non-malignant), on successive days post-seeding in a laminin-rich extracellular matrix assay. Both HMECs underwent growth arrest in G0/G1 and differentiated into polarized acini between days 5 and 7. We identified gene expression changes with the same temporal pattern in both lines. We show that genes that are significantly lower in the organized, growth arrested HMEC than in their proliferating counterparts can be used to classify breast cancer patients into poor and good prognosis groups with high accuracy. This study represents a novel unsupervised approach to identifying breast cancer markers that may be of use clinically.« less
  • Purpose: Early-stage invasive breast cancer patients have commonly undergone breast-conserving surgery and radiotherapy. In a large majority of these patients, the treatment is effective; however, a proportion will develop local recurrence. Deregulated redox systems provide cancer cells protection from increased oxidative stress, such as that induced by ionizing radiation. Therefore, the expression of redox proteins was examined in tumor specimens from this defined cohort to determine whether such expression could predict response. Methods and Materials: The nuclear and cytoplasmic expression of nine redox proteins (glutathione, glutathione reductase, glutaredoxin, glutathione peroxidase 1, 3, and 4, and glutathione S-transferase-{theta}, -{pi}, and -{alpha})more » was assessed using conventional immunohistochemistry on a tissue microarray of 224 tumors. Results: A high cytoplasmic expression of glutathione S-transferase-{theta} significantly correlated with a greater risk of local recurrence (p = .008) and, when combined with a low nuclear expression (p = .009), became an independent predictive factor (p = .002) for local recurrence. High cytoplasmic expression of glutathione S-transferase-{theta} also correlated with a worse overall survival (p = .009). Low nuclear and cytoplasmic expression of glutathione peroxidase 3 (p = .002) correlated with a greater risk of local recurrence and was an independent predictive factor (p = .005). These proteins did not correlate with tumor grade, suggesting their function might be specific to the regulation of oxidative stress rather than alterations of tumor phenotype. Only nuclear (p = .005) and cytoplasmic (p = .001) expression of glutathione peroxidase 4 correlated with the tumor grade. Conclusions: Our results support the use of redox protein expression, namely glutathione S-transferase-{theta} and glutathione peroxidase 3, to predict the response to radiotherapy in early-stage breast cancer patients. If incorporated into routine diagnostic tests, they have the potential to aid clinicians in their stratification of patients into more tailored treatment regimens. Future targeted therapies to these systems might improve the efficacy of reactive oxygen species-inducing therapies, such as radiotherapy.« less
  • Breast cancer is the most common carcinoma that metastasizes to bone. Tumor-produced parathyroid hormone-related protein (PTHrP), a known stimulator of osteoclastic bone resorption, is a major mediator of the osteolytic process in breast cancer. We have previously shown that PTHrP increases breast cancer cell proliferation, survival, migration, and pro-invasive integrin {alpha}6{beta}4 expression. To determine the role of integrin {alpha}6{beta}4 in these PTHrP-mediated effects, we utilized two strategies to modulate expression of the {alpha}6 and {beta}4 subunits in parental and PTHrP-overexpressing MDA-MB-231 and MCF-7 cells: overexpression of {alpha}6{beta}4 by transfection with constructs encoding the {alpha}6 and {beta}4 subunits, and suppression ofmore » endogenous {alpha}6{beta}4 expression by transfection with siRNAs targeting these subunits. We now show that the effects of PTHrP are mediated via upregulation of integrin {alpha}6{beta}4 expression. We also show that integrin {alpha}6{beta}4 expression is modulated at the mRNA level, indicating a transcriptional and/or post-transcriptional mechanism of action for PTHrP. PTHrP expression also increased the levels of phosphorylated Akt, with a consequent increase in the levels of phosphorylated (inactive) glycogen synthase kinase-3 (GSK-3). The role of PTHrP in breast cancer growth and metastasis may thus be mediated via upregulation of integrin {alpha}6{beta}4 expression and Akt activation, with consequent inactivation of GSK-3.« less
  • The aim was to analyze the mechanism of leptin-induced activity of telomerase in MCF-7 breast cancer cells. We found that leptin activated telomerase in a dose-dependent manner; leptin upregulated the expression of Human Telomerase Reverse Transcriptase (hTERT) at mRNA and protein levels; blockade of signal transducer and activator of transcription 3 (STAT3) phosphorylation significantly counteracted leptin-induced hTERT transcription and protein expression; chromatin immunoprecipitation analysis showed that leptin enhanced the binding of STAT3 to the hTERT promoter. This study uncovers a new mechanism of the proliferative effect of leptin on breast cancer cells and provides a new explanation of obesity-related breastmore » cancer.« less
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