Antiestrogens: Mechanisms of action and resistance in breast cancer

Benita S Katzenellenbogen, Monica M. Montano, Kirk Ekena, Mary E. Herman, Eileen M. McInerney

Research output: Contribution to journalReview article

Abstract

Antiestrogens have proven to be highly effective in the treatment of hormone-responsive breast cancer. However, resistance to antiestrogen therapy often develops. In addition, although tamoxifen-like antiestrogens are largely inhibitory and function as estrogen antagonists in breast cancer cells, they also have some estrogen-like activity in other cells of the body. Thus, recent efforts are being directed toward the development of even more tissue-selective antiestrogens, i.e. compounds that are antiestrogenic on breast and uterus while maintaining the beneficial estrogen-like actions on bone and the cardiovascular system. Efforts are also being directed toward understanding ligand structure-estrogen receptor (ER) activity relationships and characterizing the molecular changes that underlie alterations in parallel signal transduction pathways that impact on the ER. Recent findings show that antiestrogens, which are known to exert most of their effects through the ER of breast cancer cells, contact a different set of amino acids in the hormone binding domain of the ER than those contacted by estrogen, and evoke a different receptor conformation that results in reduced or no transcriptional activity on most genes. Resistance to antiestrogen therapy may develop due to changes at the level of the ER itself, and at pre- and post-receptor points in the estrogen receptor-response pathway. Resistance could arise in at least four ways: (1) ER loss or mutation; (2) Post-receptor alterations including changes in cAMP and phosphorylation pathways, or changes in coregulator and transcription factor interactions that affect the transcriptional activity of the ER; (3) Changes in growth factor production/sensitivity or paracrine cell-cell interactions; or (4) Pharmacological changes in the antiestrogen itself, including altered uptake and retention or metabolism of the antiestrogen. Model cell systems have been developed to study changes that accompany and define the antiestrogen resistant versus sensitive breast cancer phenotype. This information should lead to the development of antiestrogens with optimized tissue selectivity and agents to which resistance may develop more slowly. In addition, antiestrogens which work through somewhat different mechanisms of interaction with the ER should prove useful in treatment of some breast cancers that become resistant to a different category of antiestrogens.

Original languageEnglish (US)
Pages (from-to)23-38
Number of pages16
JournalBreast Cancer Research and Treatment
Volume44
Issue number1
DOIs
StatePublished - Jan 1 1997

Fingerprint

Estrogen Receptor Modulators
Estrogen Receptors
Breast Neoplasms
Estrogens
Hormones
Estrogen Antagonists
Tamoxifen
Cardiovascular System
Cell Communication
Uterus
Signal Transduction
Intercellular Signaling Peptides and Proteins
Breast
Transcription Factors
Phosphorylation

Keywords

  • Antiestrogen resistance
  • Antiestrogens
  • Breast cancer
  • Endocrine therapy
  • Estrogen receptor
  • Hormone sensitivity
  • Resistance
  • Tamoxifen

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Antiestrogens : Mechanisms of action and resistance in breast cancer. / Katzenellenbogen, Benita S; Montano, Monica M.; Ekena, Kirk; Herman, Mary E.; McInerney, Eileen M.

In: Breast Cancer Research and Treatment, Vol. 44, No. 1, 01.01.1997, p. 23-38.

Research output: Contribution to journalReview article

Katzenellenbogen, Benita S ; Montano, Monica M. ; Ekena, Kirk ; Herman, Mary E. ; McInerney, Eileen M. / Antiestrogens : Mechanisms of action and resistance in breast cancer. In: Breast Cancer Research and Treatment. 1997 ; Vol. 44, No. 1. pp. 23-38.
@article{11ca8bbab2344e0ca5c6da5a84b85100,
title = "Antiestrogens: Mechanisms of action and resistance in breast cancer",
abstract = "Antiestrogens have proven to be highly effective in the treatment of hormone-responsive breast cancer. However, resistance to antiestrogen therapy often develops. In addition, although tamoxifen-like antiestrogens are largely inhibitory and function as estrogen antagonists in breast cancer cells, they also have some estrogen-like activity in other cells of the body. Thus, recent efforts are being directed toward the development of even more tissue-selective antiestrogens, i.e. compounds that are antiestrogenic on breast and uterus while maintaining the beneficial estrogen-like actions on bone and the cardiovascular system. Efforts are also being directed toward understanding ligand structure-estrogen receptor (ER) activity relationships and characterizing the molecular changes that underlie alterations in parallel signal transduction pathways that impact on the ER. Recent findings show that antiestrogens, which are known to exert most of their effects through the ER of breast cancer cells, contact a different set of amino acids in the hormone binding domain of the ER than those contacted by estrogen, and evoke a different receptor conformation that results in reduced or no transcriptional activity on most genes. Resistance to antiestrogen therapy may develop due to changes at the level of the ER itself, and at pre- and post-receptor points in the estrogen receptor-response pathway. Resistance could arise in at least four ways: (1) ER loss or mutation; (2) Post-receptor alterations including changes in cAMP and phosphorylation pathways, or changes in coregulator and transcription factor interactions that affect the transcriptional activity of the ER; (3) Changes in growth factor production/sensitivity or paracrine cell-cell interactions; or (4) Pharmacological changes in the antiestrogen itself, including altered uptake and retention or metabolism of the antiestrogen. Model cell systems have been developed to study changes that accompany and define the antiestrogen resistant versus sensitive breast cancer phenotype. This information should lead to the development of antiestrogens with optimized tissue selectivity and agents to which resistance may develop more slowly. In addition, antiestrogens which work through somewhat different mechanisms of interaction with the ER should prove useful in treatment of some breast cancers that become resistant to a different category of antiestrogens.",
keywords = "Antiestrogen resistance, Antiestrogens, Breast cancer, Endocrine therapy, Estrogen receptor, Hormone sensitivity, Resistance, Tamoxifen",
author = "Katzenellenbogen, {Benita S} and Montano, {Monica M.} and Kirk Ekena and Herman, {Mary E.} and McInerney, {Eileen M.}",
year = "1997",
month = "1",
day = "1",
doi = "10.1023/A:1005835428423",
language = "English (US)",
volume = "44",
pages = "23--38",
journal = "Breast Cancer Research and Treatment",
issn = "0167-6806",
publisher = "Springer New York",
number = "1",

}

TY - JOUR

T1 - Antiestrogens

T2 - Mechanisms of action and resistance in breast cancer

AU - Katzenellenbogen, Benita S

AU - Montano, Monica M.

AU - Ekena, Kirk

AU - Herman, Mary E.

AU - McInerney, Eileen M.

PY - 1997/1/1

Y1 - 1997/1/1

N2 - Antiestrogens have proven to be highly effective in the treatment of hormone-responsive breast cancer. However, resistance to antiestrogen therapy often develops. In addition, although tamoxifen-like antiestrogens are largely inhibitory and function as estrogen antagonists in breast cancer cells, they also have some estrogen-like activity in other cells of the body. Thus, recent efforts are being directed toward the development of even more tissue-selective antiestrogens, i.e. compounds that are antiestrogenic on breast and uterus while maintaining the beneficial estrogen-like actions on bone and the cardiovascular system. Efforts are also being directed toward understanding ligand structure-estrogen receptor (ER) activity relationships and characterizing the molecular changes that underlie alterations in parallel signal transduction pathways that impact on the ER. Recent findings show that antiestrogens, which are known to exert most of their effects through the ER of breast cancer cells, contact a different set of amino acids in the hormone binding domain of the ER than those contacted by estrogen, and evoke a different receptor conformation that results in reduced or no transcriptional activity on most genes. Resistance to antiestrogen therapy may develop due to changes at the level of the ER itself, and at pre- and post-receptor points in the estrogen receptor-response pathway. Resistance could arise in at least four ways: (1) ER loss or mutation; (2) Post-receptor alterations including changes in cAMP and phosphorylation pathways, or changes in coregulator and transcription factor interactions that affect the transcriptional activity of the ER; (3) Changes in growth factor production/sensitivity or paracrine cell-cell interactions; or (4) Pharmacological changes in the antiestrogen itself, including altered uptake and retention or metabolism of the antiestrogen. Model cell systems have been developed to study changes that accompany and define the antiestrogen resistant versus sensitive breast cancer phenotype. This information should lead to the development of antiestrogens with optimized tissue selectivity and agents to which resistance may develop more slowly. In addition, antiestrogens which work through somewhat different mechanisms of interaction with the ER should prove useful in treatment of some breast cancers that become resistant to a different category of antiestrogens.

AB - Antiestrogens have proven to be highly effective in the treatment of hormone-responsive breast cancer. However, resistance to antiestrogen therapy often develops. In addition, although tamoxifen-like antiestrogens are largely inhibitory and function as estrogen antagonists in breast cancer cells, they also have some estrogen-like activity in other cells of the body. Thus, recent efforts are being directed toward the development of even more tissue-selective antiestrogens, i.e. compounds that are antiestrogenic on breast and uterus while maintaining the beneficial estrogen-like actions on bone and the cardiovascular system. Efforts are also being directed toward understanding ligand structure-estrogen receptor (ER) activity relationships and characterizing the molecular changes that underlie alterations in parallel signal transduction pathways that impact on the ER. Recent findings show that antiestrogens, which are known to exert most of their effects through the ER of breast cancer cells, contact a different set of amino acids in the hormone binding domain of the ER than those contacted by estrogen, and evoke a different receptor conformation that results in reduced or no transcriptional activity on most genes. Resistance to antiestrogen therapy may develop due to changes at the level of the ER itself, and at pre- and post-receptor points in the estrogen receptor-response pathway. Resistance could arise in at least four ways: (1) ER loss or mutation; (2) Post-receptor alterations including changes in cAMP and phosphorylation pathways, or changes in coregulator and transcription factor interactions that affect the transcriptional activity of the ER; (3) Changes in growth factor production/sensitivity or paracrine cell-cell interactions; or (4) Pharmacological changes in the antiestrogen itself, including altered uptake and retention or metabolism of the antiestrogen. Model cell systems have been developed to study changes that accompany and define the antiestrogen resistant versus sensitive breast cancer phenotype. This information should lead to the development of antiestrogens with optimized tissue selectivity and agents to which resistance may develop more slowly. In addition, antiestrogens which work through somewhat different mechanisms of interaction with the ER should prove useful in treatment of some breast cancers that become resistant to a different category of antiestrogens.

KW - Antiestrogen resistance

KW - Antiestrogens

KW - Breast cancer

KW - Endocrine therapy

KW - Estrogen receptor

KW - Hormone sensitivity

KW - Resistance

KW - Tamoxifen

UR - http://www.scopus.com/inward/record.url?scp=0031136676&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0031136676&partnerID=8YFLogxK

U2 - 10.1023/A:1005835428423

DO - 10.1023/A:1005835428423

M3 - Review article

C2 - 9164675

AN - SCOPUS:0031136676

VL - 44

SP - 23

EP - 38

JO - Breast Cancer Research and Treatment

JF - Breast Cancer Research and Treatment

SN - 0167-6806

IS - 1

ER -