Identification of gene regulation patterns underlying both oestrogen- and tamoxifen-stimulated cell growth through global gene expression profiling in breast cancer cells

Ping Fan, Heather E. Cunliffe, Obi L. Griffith, Fadeke A. Agboke, Pilar Ramos, Joe Gray, V. Craig Jordan

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Purpose A c-Src inhibitor blocks oestrogen (E2)-induced stress and converts E2 responses from inducing apoptosis to growth stimulation in E2-deprived breast cancer cells. A reprogrammed cell line, MCF-7:PF, results in a functional oestrogen receptor (ER). We addressed the question of whether the selective ER modulator 4-hydroxytamoxifen (4-OHT) could target ER to prevent E2-stimulated growth in MCF-7:PF cells. Methods Expression of mRNA was measured through real-time RT-PCR. Global gene expression profile was analysed through microarray. Transcriptome profiles were screened by RNA-sequencing. Results Unexpectedly, both 4-OHT and E2 stimulated cell growth in a concentration-dependent manner. Expression profiling showed a remarkable overlap in genes regulated in the same direction by E2 and 4-OHT. Pathway enrichment analysis of the 280 genes commonly deregulated in MCF-7:PF cells by 4-OHT and E2 revealed functions mainly related to membrane, cytoplasm and metabolic processes. Further analysis of 98 genes up-regulated by both 4-OHT and E2 uncovered a significant enrichment in genes associated with membrane remodelling, cytoskeleton reorganisation, cytoplasmic adapter proteins, cytoplasm organelle proteins and related processes. 4-OHT was more potent than E2 in up-regulating some membrane remodelling molecules, such as EHD2, FHL2, HOMER3 and RHOF. In contrast, 4-OHT acted as an antagonist to inhibit expression of the majority of enriched membrane-associated genes in wild-type MCF-7 cells. Conclusions Long-term selection pressure has changed the cell population responses to 4-OHT. Membrane-associated signalling is critical for 4-OHT-stimulated cell growth in MCF-7:PF cells. This study provides a rationale for the further investigation of target therapy for tamoxifen resistant patients.

Original languageEnglish (US)
Pages (from-to)2877-2886
Number of pages10
JournalEuropean Journal of Cancer
Volume50
Issue number16
DOIs
StatePublished - 2014

Fingerprint

Gene Expression Profiling
Tamoxifen
Estrogens
Breast Neoplasms
Growth
MCF-7 Cells
Genes
Membranes
Transcriptome
Cytoplasm
RNA Sequence Analysis
4,17 beta-dihydroxy-4-androstene-3-one
Cytoskeleton
Estrogen Receptors
Organelles
Real-Time Polymerase Chain Reaction
Proteins
Apoptosis
Pressure
Cell Line

Keywords

  • Gene expression profiling
  • Membrane-associated molecules
  • Oestrogen
  • Tamoxifen

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Identification of gene regulation patterns underlying both oestrogen- and tamoxifen-stimulated cell growth through global gene expression profiling in breast cancer cells. / Fan, Ping; Cunliffe, Heather E.; Griffith, Obi L.; Agboke, Fadeke A.; Ramos, Pilar; Gray, Joe; Jordan, V. Craig.

In: European Journal of Cancer, Vol. 50, No. 16, 2014, p. 2877-2886.

Research output: Contribution to journalArticle

Fan, Ping ; Cunliffe, Heather E. ; Griffith, Obi L. ; Agboke, Fadeke A. ; Ramos, Pilar ; Gray, Joe ; Jordan, V. Craig. / Identification of gene regulation patterns underlying both oestrogen- and tamoxifen-stimulated cell growth through global gene expression profiling in breast cancer cells. In: European Journal of Cancer. 2014 ; Vol. 50, No. 16. pp. 2877-2886.
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T1 - Identification of gene regulation patterns underlying both oestrogen- and tamoxifen-stimulated cell growth through global gene expression profiling in breast cancer cells

AU - Fan, Ping

AU - Cunliffe, Heather E.

AU - Griffith, Obi L.

AU - Agboke, Fadeke A.

AU - Ramos, Pilar

AU - Gray, Joe

AU - Jordan, V. Craig

PY - 2014

Y1 - 2014

N2 - Purpose A c-Src inhibitor blocks oestrogen (E2)-induced stress and converts E2 responses from inducing apoptosis to growth stimulation in E2-deprived breast cancer cells. A reprogrammed cell line, MCF-7:PF, results in a functional oestrogen receptor (ER). We addressed the question of whether the selective ER modulator 4-hydroxytamoxifen (4-OHT) could target ER to prevent E2-stimulated growth in MCF-7:PF cells. Methods Expression of mRNA was measured through real-time RT-PCR. Global gene expression profile was analysed through microarray. Transcriptome profiles were screened by RNA-sequencing. Results Unexpectedly, both 4-OHT and E2 stimulated cell growth in a concentration-dependent manner. Expression profiling showed a remarkable overlap in genes regulated in the same direction by E2 and 4-OHT. Pathway enrichment analysis of the 280 genes commonly deregulated in MCF-7:PF cells by 4-OHT and E2 revealed functions mainly related to membrane, cytoplasm and metabolic processes. Further analysis of 98 genes up-regulated by both 4-OHT and E2 uncovered a significant enrichment in genes associated with membrane remodelling, cytoskeleton reorganisation, cytoplasmic adapter proteins, cytoplasm organelle proteins and related processes. 4-OHT was more potent than E2 in up-regulating some membrane remodelling molecules, such as EHD2, FHL2, HOMER3 and RHOF. In contrast, 4-OHT acted as an antagonist to inhibit expression of the majority of enriched membrane-associated genes in wild-type MCF-7 cells. Conclusions Long-term selection pressure has changed the cell population responses to 4-OHT. Membrane-associated signalling is critical for 4-OHT-stimulated cell growth in MCF-7:PF cells. This study provides a rationale for the further investigation of target therapy for tamoxifen resistant patients.

AB - Purpose A c-Src inhibitor blocks oestrogen (E2)-induced stress and converts E2 responses from inducing apoptosis to growth stimulation in E2-deprived breast cancer cells. A reprogrammed cell line, MCF-7:PF, results in a functional oestrogen receptor (ER). We addressed the question of whether the selective ER modulator 4-hydroxytamoxifen (4-OHT) could target ER to prevent E2-stimulated growth in MCF-7:PF cells. Methods Expression of mRNA was measured through real-time RT-PCR. Global gene expression profile was analysed through microarray. Transcriptome profiles were screened by RNA-sequencing. Results Unexpectedly, both 4-OHT and E2 stimulated cell growth in a concentration-dependent manner. Expression profiling showed a remarkable overlap in genes regulated in the same direction by E2 and 4-OHT. Pathway enrichment analysis of the 280 genes commonly deregulated in MCF-7:PF cells by 4-OHT and E2 revealed functions mainly related to membrane, cytoplasm and metabolic processes. Further analysis of 98 genes up-regulated by both 4-OHT and E2 uncovered a significant enrichment in genes associated with membrane remodelling, cytoskeleton reorganisation, cytoplasmic adapter proteins, cytoplasm organelle proteins and related processes. 4-OHT was more potent than E2 in up-regulating some membrane remodelling molecules, such as EHD2, FHL2, HOMER3 and RHOF. In contrast, 4-OHT acted as an antagonist to inhibit expression of the majority of enriched membrane-associated genes in wild-type MCF-7 cells. Conclusions Long-term selection pressure has changed the cell population responses to 4-OHT. Membrane-associated signalling is critical for 4-OHT-stimulated cell growth in MCF-7:PF cells. This study provides a rationale for the further investigation of target therapy for tamoxifen resistant patients.

KW - Gene expression profiling

KW - Membrane-associated molecules

KW - Oestrogen

KW - Tamoxifen

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