ER Re-expression and re-sensitization to endocrine therapies in ER-negative breast cancers

Joeli A. Brinkman, Dorraya El-Ashry

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

Breast cancer is the leading cause of cancer amongst women in the westernized world. The presence or absence of ERα in breast cancers is an important prognostic indicator. About 30-40% of breast cancers lack detectable ERα protein. ERα+ breast cancers are resistant to endocrine therapies and have a worse prognosis than ERα+ breast cancers. Since expression of ERα is necessary for response to endocrine therapies, investigational studies are ongoing in order to understand the generation of the ERα-phenotype and develop interventions to restore ERα expression in ERα- breast cancers. DNA methylation and chromatin remodeling are two epigenetic mechanisms that have been linked with the lack of ERα expression and in these cases; demethylation of the ERα promoter or treatment with HDAC inhibitors shows promise in restoring ERα expression in ERα-breast cancers. Two additional potential mechanisms underlying generation of the ERα-phenotype involve E6-AP and Src, both of which have been shown to be elevated in ERα-breast cancer and can drive the proteasomal degradation of ERα. Recently, studies have demonstrated that upregulated growth factor signaling due to hyperactive MAPK activity significantly contributes to generation of the ERα-phenotype and that inhibition of MAPK activity can cause re-expression of the ERα and restore sensitivity to endocrine therapies. Given the challenges in treating ERα-breast cancer, understanding and manipulating the cellular mechanisms that effect expression of ERα are imperative in order to restore sensitivity to endocrine therapies and to design novel therapeutics for the treatment of ERα-breast cancers.

Original languageEnglish
Pages (from-to)67-78
Number of pages12
JournalJournal of Mammary Gland Biology and Neoplasia
Volume14
Issue number1
DOIs
StatePublished - Mar 5 2009

Fingerprint

Breast Neoplasms
Therapeutics
Phenotype
Investigational Therapies
Histone Deacetylase Inhibitors
Chromatin Assembly and Disassembly
DNA Methylation
Epigenomics
Intercellular Signaling Peptides and Proteins
Neoplasms
Proteins

Keywords

  • Breast cancer
  • E6-AP
  • EGFR
  • Endocrine therapy
  • Estrogen receptor
  • HDAC
  • HER2
  • MAPK
  • Src

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

ER Re-expression and re-sensitization to endocrine therapies in ER-negative breast cancers. / Brinkman, Joeli A.; El-Ashry, Dorraya.

In: Journal of Mammary Gland Biology and Neoplasia, Vol. 14, No. 1, 05.03.2009, p. 67-78.

Research output: Contribution to journalArticle

@article{42870affbbc542ac9d15aed17472cdba,
title = "ER Re-expression and re-sensitization to endocrine therapies in ER-negative breast cancers",
abstract = "Breast cancer is the leading cause of cancer amongst women in the westernized world. The presence or absence of ERα in breast cancers is an important prognostic indicator. About 30-40{\%} of breast cancers lack detectable ERα protein. ERα+ breast cancers are resistant to endocrine therapies and have a worse prognosis than ERα+ breast cancers. Since expression of ERα is necessary for response to endocrine therapies, investigational studies are ongoing in order to understand the generation of the ERα-phenotype and develop interventions to restore ERα expression in ERα- breast cancers. DNA methylation and chromatin remodeling are two epigenetic mechanisms that have been linked with the lack of ERα expression and in these cases; demethylation of the ERα promoter or treatment with HDAC inhibitors shows promise in restoring ERα expression in ERα-breast cancers. Two additional potential mechanisms underlying generation of the ERα-phenotype involve E6-AP and Src, both of which have been shown to be elevated in ERα-breast cancer and can drive the proteasomal degradation of ERα. Recently, studies have demonstrated that upregulated growth factor signaling due to hyperactive MAPK activity significantly contributes to generation of the ERα-phenotype and that inhibition of MAPK activity can cause re-expression of the ERα and restore sensitivity to endocrine therapies. Given the challenges in treating ERα-breast cancer, understanding and manipulating the cellular mechanisms that effect expression of ERα are imperative in order to restore sensitivity to endocrine therapies and to design novel therapeutics for the treatment of ERα-breast cancers.",
keywords = "Breast cancer, E6-AP, EGFR, Endocrine therapy, Estrogen receptor, HDAC, HER2, MAPK, Src",
author = "Brinkman, {Joeli A.} and Dorraya El-Ashry",
year = "2009",
month = "3",
day = "5",
doi = "10.1007/s10911-009-9113-0",
language = "English",
volume = "14",
pages = "67--78",
journal = "Journal of Mammary Gland Biology and Neoplasia",
issn = "1083-3021",
publisher = "Springer New York",
number = "1",

}

TY - JOUR

T1 - ER Re-expression and re-sensitization to endocrine therapies in ER-negative breast cancers

AU - Brinkman, Joeli A.

AU - El-Ashry, Dorraya

PY - 2009/3/5

Y1 - 2009/3/5

N2 - Breast cancer is the leading cause of cancer amongst women in the westernized world. The presence or absence of ERα in breast cancers is an important prognostic indicator. About 30-40% of breast cancers lack detectable ERα protein. ERα+ breast cancers are resistant to endocrine therapies and have a worse prognosis than ERα+ breast cancers. Since expression of ERα is necessary for response to endocrine therapies, investigational studies are ongoing in order to understand the generation of the ERα-phenotype and develop interventions to restore ERα expression in ERα- breast cancers. DNA methylation and chromatin remodeling are two epigenetic mechanisms that have been linked with the lack of ERα expression and in these cases; demethylation of the ERα promoter or treatment with HDAC inhibitors shows promise in restoring ERα expression in ERα-breast cancers. Two additional potential mechanisms underlying generation of the ERα-phenotype involve E6-AP and Src, both of which have been shown to be elevated in ERα-breast cancer and can drive the proteasomal degradation of ERα. Recently, studies have demonstrated that upregulated growth factor signaling due to hyperactive MAPK activity significantly contributes to generation of the ERα-phenotype and that inhibition of MAPK activity can cause re-expression of the ERα and restore sensitivity to endocrine therapies. Given the challenges in treating ERα-breast cancer, understanding and manipulating the cellular mechanisms that effect expression of ERα are imperative in order to restore sensitivity to endocrine therapies and to design novel therapeutics for the treatment of ERα-breast cancers.

AB - Breast cancer is the leading cause of cancer amongst women in the westernized world. The presence or absence of ERα in breast cancers is an important prognostic indicator. About 30-40% of breast cancers lack detectable ERα protein. ERα+ breast cancers are resistant to endocrine therapies and have a worse prognosis than ERα+ breast cancers. Since expression of ERα is necessary for response to endocrine therapies, investigational studies are ongoing in order to understand the generation of the ERα-phenotype and develop interventions to restore ERα expression in ERα- breast cancers. DNA methylation and chromatin remodeling are two epigenetic mechanisms that have been linked with the lack of ERα expression and in these cases; demethylation of the ERα promoter or treatment with HDAC inhibitors shows promise in restoring ERα expression in ERα-breast cancers. Two additional potential mechanisms underlying generation of the ERα-phenotype involve E6-AP and Src, both of which have been shown to be elevated in ERα-breast cancer and can drive the proteasomal degradation of ERα. Recently, studies have demonstrated that upregulated growth factor signaling due to hyperactive MAPK activity significantly contributes to generation of the ERα-phenotype and that inhibition of MAPK activity can cause re-expression of the ERα and restore sensitivity to endocrine therapies. Given the challenges in treating ERα-breast cancer, understanding and manipulating the cellular mechanisms that effect expression of ERα are imperative in order to restore sensitivity to endocrine therapies and to design novel therapeutics for the treatment of ERα-breast cancers.

KW - Breast cancer

KW - E6-AP

KW - EGFR

KW - Endocrine therapy

KW - Estrogen receptor

KW - HDAC

KW - HER2

KW - MAPK

KW - Src

UR - http://www.scopus.com/inward/record.url?scp=62549106985&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=62549106985&partnerID=8YFLogxK

U2 - 10.1007/s10911-009-9113-0

DO - 10.1007/s10911-009-9113-0

M3 - Article

C2 - 19263197

AN - SCOPUS:62549106985

VL - 14

SP - 67

EP - 78

JO - Journal of Mammary Gland Biology and Neoplasia

JF - Journal of Mammary Gland Biology and Neoplasia

SN - 1083-3021

IS - 1

ER -