Comparative gene expression profiling reveals partially overlapping but distinct genomic actions of different antiestrogens in human breast cancer cells

Claudio Scafoglio, Concetta Ambrosino, Luigi Cicatiello, Lucia Altucci, Mario Ardovino, Paola Bontempo, Nicola Medici, Anna Maria Molinari, Angela Nebbioso, Angelo Facchiano, Raffaele A. Calogero, Ran Elkon, Nadia Menini, Riccardo Ponzone, Nicoletta Biglia, Piero Sismondi, Michele De Bortoli, Alessandro Weisz

Research output: Contribution to journalArticle

Abstract

Antiestrogens used for breast cancer (BC) treatment differ among each other for the ability to affect estrogen receptor (ER) activity and thereby inhibit hormone-responsive cell functions and viability. We used high-density cDNA microarrays for a comprehensive definition of the gene pathways affected by 17β-estradiol (E2), ICI 182,780 (ICI), 4OH-tamoxifen (Tamoxifen), and raloxifene (RAL) in ER-positive ZR-75.1 cells, a suitable model to investigate estrogen and antiestrogen actions in hormone-responsive BC. The expression of 601 genes was significantly affected by E2 in these cells; in silico analysis reveals that 86 among them include one or more potential ER binding site within or near the promoter and that the binding site signatures for E2F-1, NF-Y, and NRF-1 transcription factors are significantly enriched in the promoters of genes induced by estrogen treatment, while those for CAC-binding protein and LF-A1 in those repressed by the hormone, pointing to novel transcriptional effectors of secondary responses to estrogen in BC cells. Interestingly, expression of 176 E2-regulated mRNAs was unaffected by any of the antiestrogens tested, despite the fact that under the same conditions the transcriptional and cell cycle stimulatory activities of ER were inhibited. On the other hand, of 373 antiestrogen-responsive genes identified here, 52 were unresponsive to estrogen and 25% responded specifically to only one of the compounds tested, revealing non-overlapping and clearly distinguishable effects of the different antiestrogens in BC cells. As some of these differences reflect specificities of the mechanism of action of the antiestrogens tested, we propose to exploit this gene set for characterization of novel hormonal antagonists and selective estrogen receptor modulators (SERMs) and as a tool for testing new associations of antiestrogens, more effective against BC.

Original languageEnglish
Pages (from-to)1163-1184
Number of pages22
JournalJournal of Cellular Biochemistry
Volume98
Issue number5
DOIs
Publication statusPublished - Aug 1 2006

Fingerprint

Estrogen Receptor Modulators
Gene Expression Profiling
Gene expression
Cells
Breast Neoplasms
Genes
Estrogen Receptors
Estrogens
Hormones
Binding Sites
Selective Estrogen Receptor Modulators
Oncology
Tamoxifen
Microarrays
Oligonucleotide Array Sequence Analysis
Computer Simulation
Estradiol
Cell Survival
Cell Cycle
Carrier Proteins

Keywords

  • Breast cancer
  • cDNA microarrays
  • Estrogen
  • ICI 182,780
  • Raloxifene
  • Tamoxifen

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology

Cite this

Comparative gene expression profiling reveals partially overlapping but distinct genomic actions of different antiestrogens in human breast cancer cells. / Scafoglio, Claudio; Ambrosino, Concetta; Cicatiello, Luigi; Altucci, Lucia; Ardovino, Mario; Bontempo, Paola; Medici, Nicola; Molinari, Anna Maria; Nebbioso, Angela; Facchiano, Angelo; Calogero, Raffaele A.; Elkon, Ran; Menini, Nadia; Ponzone, Riccardo; Biglia, Nicoletta; Sismondi, Piero; De Bortoli, Michele; Weisz, Alessandro.

In: Journal of Cellular Biochemistry, Vol. 98, No. 5, 01.08.2006, p. 1163-1184.

Research output: Contribution to journalArticle

Scafoglio, C, Ambrosino, C, Cicatiello, L, Altucci, L, Ardovino, M, Bontempo, P, Medici, N, Molinari, AM, Nebbioso, A, Facchiano, A, Calogero, RA, Elkon, R, Menini, N, Ponzone, R, Biglia, N, Sismondi, P, De Bortoli, M & Weisz, A 2006, 'Comparative gene expression profiling reveals partially overlapping but distinct genomic actions of different antiestrogens in human breast cancer cells', Journal of Cellular Biochemistry, vol. 98, no. 5, pp. 1163-1184. https://doi.org/10.1002/jcb.20820
Scafoglio, Claudio ; Ambrosino, Concetta ; Cicatiello, Luigi ; Altucci, Lucia ; Ardovino, Mario ; Bontempo, Paola ; Medici, Nicola ; Molinari, Anna Maria ; Nebbioso, Angela ; Facchiano, Angelo ; Calogero, Raffaele A. ; Elkon, Ran ; Menini, Nadia ; Ponzone, Riccardo ; Biglia, Nicoletta ; Sismondi, Piero ; De Bortoli, Michele ; Weisz, Alessandro. / Comparative gene expression profiling reveals partially overlapping but distinct genomic actions of different antiestrogens in human breast cancer cells. In: Journal of Cellular Biochemistry. 2006 ; Vol. 98, No. 5. pp. 1163-1184.
@article{54d11aaa3b4b481784a24b93ca2df1ec,
title = "Comparative gene expression profiling reveals partially overlapping but distinct genomic actions of different antiestrogens in human breast cancer cells",
abstract = "Antiestrogens used for breast cancer (BC) treatment differ among each other for the ability to affect estrogen receptor (ER) activity and thereby inhibit hormone-responsive cell functions and viability. We used high-density cDNA microarrays for a comprehensive definition of the gene pathways affected by 17β-estradiol (E2), ICI 182,780 (ICI), 4OH-tamoxifen (Tamoxifen), and raloxifene (RAL) in ER-positive ZR-75.1 cells, a suitable model to investigate estrogen and antiestrogen actions in hormone-responsive BC. The expression of 601 genes was significantly affected by E2 in these cells; in silico analysis reveals that 86 among them include one or more potential ER binding site within or near the promoter and that the binding site signatures for E2F-1, NF-Y, and NRF-1 transcription factors are significantly enriched in the promoters of genes induced by estrogen treatment, while those for CAC-binding protein and LF-A1 in those repressed by the hormone, pointing to novel transcriptional effectors of secondary responses to estrogen in BC cells. Interestingly, expression of 176 E2-regulated mRNAs was unaffected by any of the antiestrogens tested, despite the fact that under the same conditions the transcriptional and cell cycle stimulatory activities of ER were inhibited. On the other hand, of 373 antiestrogen-responsive genes identified here, 52 were unresponsive to estrogen and 25{\%} responded specifically to only one of the compounds tested, revealing non-overlapping and clearly distinguishable effects of the different antiestrogens in BC cells. As some of these differences reflect specificities of the mechanism of action of the antiestrogens tested, we propose to exploit this gene set for characterization of novel hormonal antagonists and selective estrogen receptor modulators (SERMs) and as a tool for testing new associations of antiestrogens, more effective against BC.",
keywords = "Breast cancer, cDNA microarrays, Estrogen, ICI 182,780, Raloxifene, Tamoxifen",
author = "Claudio Scafoglio and Concetta Ambrosino and Luigi Cicatiello and Lucia Altucci and Mario Ardovino and Paola Bontempo and Nicola Medici and Molinari, {Anna Maria} and Angela Nebbioso and Angelo Facchiano and Calogero, {Raffaele A.} and Ran Elkon and Nadia Menini and Riccardo Ponzone and Nicoletta Biglia and Piero Sismondi and {De Bortoli}, Michele and Alessandro Weisz",
year = "2006",
month = "8",
day = "1",
doi = "10.1002/jcb.20820",
language = "English",
volume = "98",
pages = "1163--1184",
journal = "Journal of Cellular Biochemistry",
issn = "0730-2312",
publisher = "Wiley-Liss Inc.",
number = "5",

}

TY - JOUR

T1 - Comparative gene expression profiling reveals partially overlapping but distinct genomic actions of different antiestrogens in human breast cancer cells

AU - Scafoglio, Claudio

AU - Ambrosino, Concetta

AU - Cicatiello, Luigi

AU - Altucci, Lucia

AU - Ardovino, Mario

AU - Bontempo, Paola

AU - Medici, Nicola

AU - Molinari, Anna Maria

AU - Nebbioso, Angela

AU - Facchiano, Angelo

AU - Calogero, Raffaele A.

AU - Elkon, Ran

AU - Menini, Nadia

AU - Ponzone, Riccardo

AU - Biglia, Nicoletta

AU - Sismondi, Piero

AU - De Bortoli, Michele

AU - Weisz, Alessandro

PY - 2006/8/1

Y1 - 2006/8/1

N2 - Antiestrogens used for breast cancer (BC) treatment differ among each other for the ability to affect estrogen receptor (ER) activity and thereby inhibit hormone-responsive cell functions and viability. We used high-density cDNA microarrays for a comprehensive definition of the gene pathways affected by 17β-estradiol (E2), ICI 182,780 (ICI), 4OH-tamoxifen (Tamoxifen), and raloxifene (RAL) in ER-positive ZR-75.1 cells, a suitable model to investigate estrogen and antiestrogen actions in hormone-responsive BC. The expression of 601 genes was significantly affected by E2 in these cells; in silico analysis reveals that 86 among them include one or more potential ER binding site within or near the promoter and that the binding site signatures for E2F-1, NF-Y, and NRF-1 transcription factors are significantly enriched in the promoters of genes induced by estrogen treatment, while those for CAC-binding protein and LF-A1 in those repressed by the hormone, pointing to novel transcriptional effectors of secondary responses to estrogen in BC cells. Interestingly, expression of 176 E2-regulated mRNAs was unaffected by any of the antiestrogens tested, despite the fact that under the same conditions the transcriptional and cell cycle stimulatory activities of ER were inhibited. On the other hand, of 373 antiestrogen-responsive genes identified here, 52 were unresponsive to estrogen and 25% responded specifically to only one of the compounds tested, revealing non-overlapping and clearly distinguishable effects of the different antiestrogens in BC cells. As some of these differences reflect specificities of the mechanism of action of the antiestrogens tested, we propose to exploit this gene set for characterization of novel hormonal antagonists and selective estrogen receptor modulators (SERMs) and as a tool for testing new associations of antiestrogens, more effective against BC.

AB - Antiestrogens used for breast cancer (BC) treatment differ among each other for the ability to affect estrogen receptor (ER) activity and thereby inhibit hormone-responsive cell functions and viability. We used high-density cDNA microarrays for a comprehensive definition of the gene pathways affected by 17β-estradiol (E2), ICI 182,780 (ICI), 4OH-tamoxifen (Tamoxifen), and raloxifene (RAL) in ER-positive ZR-75.1 cells, a suitable model to investigate estrogen and antiestrogen actions in hormone-responsive BC. The expression of 601 genes was significantly affected by E2 in these cells; in silico analysis reveals that 86 among them include one or more potential ER binding site within or near the promoter and that the binding site signatures for E2F-1, NF-Y, and NRF-1 transcription factors are significantly enriched in the promoters of genes induced by estrogen treatment, while those for CAC-binding protein and LF-A1 in those repressed by the hormone, pointing to novel transcriptional effectors of secondary responses to estrogen in BC cells. Interestingly, expression of 176 E2-regulated mRNAs was unaffected by any of the antiestrogens tested, despite the fact that under the same conditions the transcriptional and cell cycle stimulatory activities of ER were inhibited. On the other hand, of 373 antiestrogen-responsive genes identified here, 52 were unresponsive to estrogen and 25% responded specifically to only one of the compounds tested, revealing non-overlapping and clearly distinguishable effects of the different antiestrogens in BC cells. As some of these differences reflect specificities of the mechanism of action of the antiestrogens tested, we propose to exploit this gene set for characterization of novel hormonal antagonists and selective estrogen receptor modulators (SERMs) and as a tool for testing new associations of antiestrogens, more effective against BC.

KW - Breast cancer

KW - cDNA microarrays

KW - Estrogen

KW - ICI 182,780

KW - Raloxifene

KW - Tamoxifen

UR - http://www.scopus.com/inward/record.url?scp=33746416623&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33746416623&partnerID=8YFLogxK

U2 - 10.1002/jcb.20820

DO - 10.1002/jcb.20820

M3 - Article

C2 - 16514628

AN - SCOPUS:33746416623

VL - 98

SP - 1163

EP - 1184

JO - Journal of Cellular Biochemistry

JF - Journal of Cellular Biochemistry

SN - 0730-2312

IS - 5

ER -