A systems analysis of the chemosensitivity of breast cancer cells to the polyamine analogue PG-11047

Wen Lin Kuo, Debopriya Das, Safiyyah Ziyad, Sanchita Bhattacharya, William J. Gibb, Laura Heiser, Anguraj Sadanandam, Gerald V. Fontenay, Zhi Hu, Nicholas J. Wang, Nora Bayani, Heidi Feiler, Richard M. Neve, Andrew J. Wyrobek, Paul Spellman, Laurence J. Marton, Joe Gray

Research output: Contribution to journalArticle

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Abstract

Background: Polyamines regulate important cellular functions and polyamine dysregulation frequently occurs in cancer. The objective of this study was to use a systems approach to study the relative effects of PG-11047, a polyamine analogue, across breast cancer cells derived from different patients and to identify genetic markers associated with differential cytotoxicity.Methods: A panel of 48 breast cell lines that mirror many transcriptional and genomic features present in primary human breast tumours were used to study the antiproliferative activity of PG-11047. Sensitive cell lines were further examined for cell cycle distribution and apoptotic response. Cell line responses, quantified by the GI50 (dose required for 50% relative growth inhibition) were correlated with the omic profiles of the cell lines to identify markers that predict response and cellular functions associated with drug sensitivity.Results: The concentrations of PG-11047 needed to inhibit growth of members of the panel of breast cell lines varied over a wide range, with basal-like cell lines being inhibited at lower concentrations than the luminal cell lines. Sensitive cell lines showed a significant decrease in S phase fraction at doses that produced little apoptosis. Correlation of the GI50 values with the omic profiles of the cell lines identified genomic, transcriptional and proteomic variables associated with response.Conclusions: A 13-gene transcriptional marker set was developed as a predictor of response to PG-11047 that warrants clinical evaluation. Analyses of the pathways, networks and genes associated with response to PG-11047 suggest that response may be influenced by interferon signalling and differential inhibition of aspects of motility and epithelial to mesenchymal transition.See the related commentary by Benes and Settleman: http://www.biomedcentral.com/1741-7015/7/78.

Original languageEnglish (US)
Article number77
JournalBMC Medicine
Volume7
DOIs
StatePublished - Dec 14 2009
Externally publishedYes

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Polyamines
Systems Analysis
Breast Neoplasms
Cell Line
Breast
(N(1),N(12))bis(ethyl)-6,7-dehydrospermine
Epithelial-Mesenchymal Transition
Gene Regulatory Networks
Growth
S Phase
Genetic Markers
Proteomics
Interferons
Cell Cycle
Apoptosis

ASJC Scopus subject areas

  • Medicine(all)

Cite this

A systems analysis of the chemosensitivity of breast cancer cells to the polyamine analogue PG-11047. / Kuo, Wen Lin; Das, Debopriya; Ziyad, Safiyyah; Bhattacharya, Sanchita; Gibb, William J.; Heiser, Laura; Sadanandam, Anguraj; Fontenay, Gerald V.; Hu, Zhi; Wang, Nicholas J.; Bayani, Nora; Feiler, Heidi; Neve, Richard M.; Wyrobek, Andrew J.; Spellman, Paul; Marton, Laurence J.; Gray, Joe.

In: BMC Medicine, Vol. 7, 77, 14.12.2009.

Research output: Contribution to journalArticle

Kuo, WL, Das, D, Ziyad, S, Bhattacharya, S, Gibb, WJ, Heiser, L, Sadanandam, A, Fontenay, GV, Hu, Z, Wang, NJ, Bayani, N, Feiler, H, Neve, RM, Wyrobek, AJ, Spellman, P, Marton, LJ & Gray, J 2009, 'A systems analysis of the chemosensitivity of breast cancer cells to the polyamine analogue PG-11047', BMC Medicine, vol. 7, 77. https://doi.org/10.1186/1741-7015-7-77
Kuo, Wen Lin ; Das, Debopriya ; Ziyad, Safiyyah ; Bhattacharya, Sanchita ; Gibb, William J. ; Heiser, Laura ; Sadanandam, Anguraj ; Fontenay, Gerald V. ; Hu, Zhi ; Wang, Nicholas J. ; Bayani, Nora ; Feiler, Heidi ; Neve, Richard M. ; Wyrobek, Andrew J. ; Spellman, Paul ; Marton, Laurence J. ; Gray, Joe. / A systems analysis of the chemosensitivity of breast cancer cells to the polyamine analogue PG-11047. In: BMC Medicine. 2009 ; Vol. 7.
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abstract = "Background: Polyamines regulate important cellular functions and polyamine dysregulation frequently occurs in cancer. The objective of this study was to use a systems approach to study the relative effects of PG-11047, a polyamine analogue, across breast cancer cells derived from different patients and to identify genetic markers associated with differential cytotoxicity.Methods: A panel of 48 breast cell lines that mirror many transcriptional and genomic features present in primary human breast tumours were used to study the antiproliferative activity of PG-11047. Sensitive cell lines were further examined for cell cycle distribution and apoptotic response. Cell line responses, quantified by the GI50 (dose required for 50{\%} relative growth inhibition) were correlated with the omic profiles of the cell lines to identify markers that predict response and cellular functions associated with drug sensitivity.Results: The concentrations of PG-11047 needed to inhibit growth of members of the panel of breast cell lines varied over a wide range, with basal-like cell lines being inhibited at lower concentrations than the luminal cell lines. Sensitive cell lines showed a significant decrease in S phase fraction at doses that produced little apoptosis. Correlation of the GI50 values with the omic profiles of the cell lines identified genomic, transcriptional and proteomic variables associated with response.Conclusions: A 13-gene transcriptional marker set was developed as a predictor of response to PG-11047 that warrants clinical evaluation. Analyses of the pathways, networks and genes associated with response to PG-11047 suggest that response may be influenced by interferon signalling and differential inhibition of aspects of motility and epithelial to mesenchymal transition.See the related commentary by Benes and Settleman: http://www.biomedcentral.com/1741-7015/7/78.",
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T1 - A systems analysis of the chemosensitivity of breast cancer cells to the polyamine analogue PG-11047

AU - Kuo, Wen Lin

AU - Das, Debopriya

AU - Ziyad, Safiyyah

AU - Bhattacharya, Sanchita

AU - Gibb, William J.

AU - Heiser, Laura

AU - Sadanandam, Anguraj

AU - Fontenay, Gerald V.

AU - Hu, Zhi

AU - Wang, Nicholas J.

AU - Bayani, Nora

AU - Feiler, Heidi

AU - Neve, Richard M.

AU - Wyrobek, Andrew J.

AU - Spellman, Paul

AU - Marton, Laurence J.

AU - Gray, Joe

PY - 2009/12/14

Y1 - 2009/12/14

N2 - Background: Polyamines regulate important cellular functions and polyamine dysregulation frequently occurs in cancer. The objective of this study was to use a systems approach to study the relative effects of PG-11047, a polyamine analogue, across breast cancer cells derived from different patients and to identify genetic markers associated with differential cytotoxicity.Methods: A panel of 48 breast cell lines that mirror many transcriptional and genomic features present in primary human breast tumours were used to study the antiproliferative activity of PG-11047. Sensitive cell lines were further examined for cell cycle distribution and apoptotic response. Cell line responses, quantified by the GI50 (dose required for 50% relative growth inhibition) were correlated with the omic profiles of the cell lines to identify markers that predict response and cellular functions associated with drug sensitivity.Results: The concentrations of PG-11047 needed to inhibit growth of members of the panel of breast cell lines varied over a wide range, with basal-like cell lines being inhibited at lower concentrations than the luminal cell lines. Sensitive cell lines showed a significant decrease in S phase fraction at doses that produced little apoptosis. Correlation of the GI50 values with the omic profiles of the cell lines identified genomic, transcriptional and proteomic variables associated with response.Conclusions: A 13-gene transcriptional marker set was developed as a predictor of response to PG-11047 that warrants clinical evaluation. Analyses of the pathways, networks and genes associated with response to PG-11047 suggest that response may be influenced by interferon signalling and differential inhibition of aspects of motility and epithelial to mesenchymal transition.See the related commentary by Benes and Settleman: http://www.biomedcentral.com/1741-7015/7/78.

AB - Background: Polyamines regulate important cellular functions and polyamine dysregulation frequently occurs in cancer. The objective of this study was to use a systems approach to study the relative effects of PG-11047, a polyamine analogue, across breast cancer cells derived from different patients and to identify genetic markers associated with differential cytotoxicity.Methods: A panel of 48 breast cell lines that mirror many transcriptional and genomic features present in primary human breast tumours were used to study the antiproliferative activity of PG-11047. Sensitive cell lines were further examined for cell cycle distribution and apoptotic response. Cell line responses, quantified by the GI50 (dose required for 50% relative growth inhibition) were correlated with the omic profiles of the cell lines to identify markers that predict response and cellular functions associated with drug sensitivity.Results: The concentrations of PG-11047 needed to inhibit growth of members of the panel of breast cell lines varied over a wide range, with basal-like cell lines being inhibited at lower concentrations than the luminal cell lines. Sensitive cell lines showed a significant decrease in S phase fraction at doses that produced little apoptosis. Correlation of the GI50 values with the omic profiles of the cell lines identified genomic, transcriptional and proteomic variables associated with response.Conclusions: A 13-gene transcriptional marker set was developed as a predictor of response to PG-11047 that warrants clinical evaluation. Analyses of the pathways, networks and genes associated with response to PG-11047 suggest that response may be influenced by interferon signalling and differential inhibition of aspects of motility and epithelial to mesenchymal transition.See the related commentary by Benes and Settleman: http://www.biomedcentral.com/1741-7015/7/78.

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