Selective Estrogen Receptor Modulators: Discrimination of Agonistic versus Antagonistic Activities by Gene Expression Profiling in Breast Cancer Cells

Jonna Frasor, Fabio Stossi, Jeanne M. Danes, Barry Komm, C. Richard Lyttle, Benita S. Katzenellenbogen

Research output: Contribution to journalArticle

Abstract

Selective estrogen receptor modulators (SERMs) such as tamoxifen are effective in the treatment of many estrogen receptor-positive breast cancers and have also proven to be effective in the prevention of breast cancer in women at high risk for the disease. The comparative abilities of tamoxifen versus raloxifene in breast cancer prevention are currently being compared in the Study of Tamoxifen and Raloxifene trial. To better understand the actions of these compounds in breast cancer, we have examined their effects on the expression of ∼12,000 genes, using Affymetrix GeneChip microarrays, with quantitative PCR verification in many cases, categorizing their actions as agonist, antagonist, or partial agonist/antagonist. Analysis of gene stimulation and inhibition by the SERMs trans-hydroxytamoxifen (TOT) and raloxifene (Ral) or ICI 182,780 (ICI) and by estradiol (E2) in estrogen receptor-containing MCF-7 human breast cancer cells revealed that (a) TOT was the most E2-like of the three compounds, (b) all three compounds either partially or fully antagonized the action of E2 on most genes, with the order of antagonist activity being ICI > Ral > TOT, (c) TOT and Rai, but not ICI, displayed partial agonist/partial antagonist activity on a number of E2-regulated genes, (d) several stimulatory cell cycle-related genes were down-regulated exclusively by ICI, (e) the estrogen-like activity of Ral nearly always overlapped with that of TOT, indicating that Ral has little unique agonist activity different from that of TOT, and (f) some genes were specifically up-regulated by TOT but not Ral, ICI, or E2. Hence, gene expression profiling can discern fundamental differences among SERMs and provides insight into the distinct biologies of TOT, Ral, and ICI in breast cancer.

Original languageEnglish (US)
Pages (from-to)1522-1533
Number of pages12
JournalCancer Research
Volume64
Issue number4
DOIs
StatePublished - Feb 15 2004

Fingerprint

Selective Estrogen Receptor Modulators
Gene Expression Profiling
Breast Neoplasms
Tamoxifen
Estrogen Receptors
Genes
cdc Genes
Gene Order
Raloxifene Hydrochloride
Estradiol
Estrogens
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Selective Estrogen Receptor Modulators : Discrimination of Agonistic versus Antagonistic Activities by Gene Expression Profiling in Breast Cancer Cells. / Frasor, Jonna; Stossi, Fabio; Danes, Jeanne M.; Komm, Barry; Lyttle, C. Richard; Katzenellenbogen, Benita S.

In: Cancer Research, Vol. 64, No. 4, 15.02.2004, p. 1522-1533.

Research output: Contribution to journalArticle

Frasor, Jonna ; Stossi, Fabio ; Danes, Jeanne M. ; Komm, Barry ; Lyttle, C. Richard ; Katzenellenbogen, Benita S. / Selective Estrogen Receptor Modulators : Discrimination of Agonistic versus Antagonistic Activities by Gene Expression Profiling in Breast Cancer Cells. In: Cancer Research. 2004 ; Vol. 64, No. 4. pp. 1522-1533.
@article{2418822135b44981a7c50aa355d5d3ee,
title = "Selective Estrogen Receptor Modulators: Discrimination of Agonistic versus Antagonistic Activities by Gene Expression Profiling in Breast Cancer Cells",
abstract = "Selective estrogen receptor modulators (SERMs) such as tamoxifen are effective in the treatment of many estrogen receptor-positive breast cancers and have also proven to be effective in the prevention of breast cancer in women at high risk for the disease. The comparative abilities of tamoxifen versus raloxifene in breast cancer prevention are currently being compared in the Study of Tamoxifen and Raloxifene trial. To better understand the actions of these compounds in breast cancer, we have examined their effects on the expression of ∼12,000 genes, using Affymetrix GeneChip microarrays, with quantitative PCR verification in many cases, categorizing their actions as agonist, antagonist, or partial agonist/antagonist. Analysis of gene stimulation and inhibition by the SERMs trans-hydroxytamoxifen (TOT) and raloxifene (Ral) or ICI 182,780 (ICI) and by estradiol (E2) in estrogen receptor-containing MCF-7 human breast cancer cells revealed that (a) TOT was the most E2-like of the three compounds, (b) all three compounds either partially or fully antagonized the action of E2 on most genes, with the order of antagonist activity being ICI > Ral > TOT, (c) TOT and Rai, but not ICI, displayed partial agonist/partial antagonist activity on a number of E2-regulated genes, (d) several stimulatory cell cycle-related genes were down-regulated exclusively by ICI, (e) the estrogen-like activity of Ral nearly always overlapped with that of TOT, indicating that Ral has little unique agonist activity different from that of TOT, and (f) some genes were specifically up-regulated by TOT but not Ral, ICI, or E2. Hence, gene expression profiling can discern fundamental differences among SERMs and provides insight into the distinct biologies of TOT, Ral, and ICI in breast cancer.",
author = "Jonna Frasor and Fabio Stossi and Danes, {Jeanne M.} and Barry Komm and Lyttle, {C. Richard} and Katzenellenbogen, {Benita S.}",
year = "2004",
month = "2",
day = "15",
doi = "10.1158/0008-5472.CAN-03-3326",
language = "English (US)",
volume = "64",
pages = "1522--1533",
journal = "Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "4",

}

TY - JOUR

T1 - Selective Estrogen Receptor Modulators

T2 - Discrimination of Agonistic versus Antagonistic Activities by Gene Expression Profiling in Breast Cancer Cells

AU - Frasor, Jonna

AU - Stossi, Fabio

AU - Danes, Jeanne M.

AU - Komm, Barry

AU - Lyttle, C. Richard

AU - Katzenellenbogen, Benita S.

PY - 2004/2/15

Y1 - 2004/2/15

N2 - Selective estrogen receptor modulators (SERMs) such as tamoxifen are effective in the treatment of many estrogen receptor-positive breast cancers and have also proven to be effective in the prevention of breast cancer in women at high risk for the disease. The comparative abilities of tamoxifen versus raloxifene in breast cancer prevention are currently being compared in the Study of Tamoxifen and Raloxifene trial. To better understand the actions of these compounds in breast cancer, we have examined their effects on the expression of ∼12,000 genes, using Affymetrix GeneChip microarrays, with quantitative PCR verification in many cases, categorizing their actions as agonist, antagonist, or partial agonist/antagonist. Analysis of gene stimulation and inhibition by the SERMs trans-hydroxytamoxifen (TOT) and raloxifene (Ral) or ICI 182,780 (ICI) and by estradiol (E2) in estrogen receptor-containing MCF-7 human breast cancer cells revealed that (a) TOT was the most E2-like of the three compounds, (b) all three compounds either partially or fully antagonized the action of E2 on most genes, with the order of antagonist activity being ICI > Ral > TOT, (c) TOT and Rai, but not ICI, displayed partial agonist/partial antagonist activity on a number of E2-regulated genes, (d) several stimulatory cell cycle-related genes were down-regulated exclusively by ICI, (e) the estrogen-like activity of Ral nearly always overlapped with that of TOT, indicating that Ral has little unique agonist activity different from that of TOT, and (f) some genes were specifically up-regulated by TOT but not Ral, ICI, or E2. Hence, gene expression profiling can discern fundamental differences among SERMs and provides insight into the distinct biologies of TOT, Ral, and ICI in breast cancer.

AB - Selective estrogen receptor modulators (SERMs) such as tamoxifen are effective in the treatment of many estrogen receptor-positive breast cancers and have also proven to be effective in the prevention of breast cancer in women at high risk for the disease. The comparative abilities of tamoxifen versus raloxifene in breast cancer prevention are currently being compared in the Study of Tamoxifen and Raloxifene trial. To better understand the actions of these compounds in breast cancer, we have examined their effects on the expression of ∼12,000 genes, using Affymetrix GeneChip microarrays, with quantitative PCR verification in many cases, categorizing their actions as agonist, antagonist, or partial agonist/antagonist. Analysis of gene stimulation and inhibition by the SERMs trans-hydroxytamoxifen (TOT) and raloxifene (Ral) or ICI 182,780 (ICI) and by estradiol (E2) in estrogen receptor-containing MCF-7 human breast cancer cells revealed that (a) TOT was the most E2-like of the three compounds, (b) all three compounds either partially or fully antagonized the action of E2 on most genes, with the order of antagonist activity being ICI > Ral > TOT, (c) TOT and Rai, but not ICI, displayed partial agonist/partial antagonist activity on a number of E2-regulated genes, (d) several stimulatory cell cycle-related genes were down-regulated exclusively by ICI, (e) the estrogen-like activity of Ral nearly always overlapped with that of TOT, indicating that Ral has little unique agonist activity different from that of TOT, and (f) some genes were specifically up-regulated by TOT but not Ral, ICI, or E2. Hence, gene expression profiling can discern fundamental differences among SERMs and provides insight into the distinct biologies of TOT, Ral, and ICI in breast cancer.

UR - http://www.scopus.com/inward/record.url?scp=1242338758&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=1242338758&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-03-3326

DO - 10.1158/0008-5472.CAN-03-3326

M3 - Article

C2 - 14973112

AN - SCOPUS:1242338758

VL - 64

SP - 1522

EP - 1533

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 4

ER -