Interplay between steroid hormone activation of the unfolded protein response and nuclear receptor action

Xiaobin Zheng, Neal Andruska, Liqun Yu, Chengjian Mao, Ji Eun Kim, Mara Livezey, William G. Helferich, David J. Shapiro

Research output: Contribution to journalReview article

Abstract

To identify new pathways of estrogen action and novel estrogen receptor α (ERα) biomodulators, we performed high throughput screening and used follow on assays and bioinformatics to identify small molecule ERα inhibitors with a novel mode of action. These studies led to identification of rapid extranuclear activation of the endoplasmic reticulum stress sensor, the unfolded protein response (UPR), as a new pathway of estrogen-ERα action. Moreover, increasing evidence indicates that the mechanism underlying anticipatory activation of the UPR is shared among steroid and peptide hormones and is conserved from insects to humans. It is likely that this newly unveiled extranuclear pathway is used by diverse mitogenic hormones to prepare cells for the increased protein folding load that will occur during subsequent cell proliferation. Demonstrating biological relevance, elevated expression of a UPR gene signature in ERα positive breast cancer is a powerful new prognostic marker tightly correlated with subsequent resistance to tamoxifen, tumor recurrence and poor survival. In addition, overexpression of epidermal growth factor receptor and HER2/neu is positively correlated with increased UPR activation in breast cancer. This review describes recent research that demonstrates the importance of anticipatory UPR activation in therapy resistant tumors and discusses a promising small molecule biomodulator that inhibits tumor growth by tuning this UPR signaling pathway.

Original languageEnglish (US)
Pages (from-to)2-6
Number of pages5
JournalSteroids
Volume114
DOIs
StatePublished - Jan 1 2016

Fingerprint

Steroid hormones
Unfolded Protein Response
Cytoplasmic and Nuclear Receptors
Chemical activation
Steroids
Hormones
Estrogen Receptors
Tumors
Proteins
Immunologic Factors
Estrogens
Breast Neoplasms
Protein folding
Neoplasms
Molecules
Endoplasmic Reticulum Stress
Peptide Hormones
Protein Folding
Cell proliferation
Tamoxifen

Keywords

  • Breast cancer
  • Cancer
  • Cell death
  • Hormone action
  • Steroid receptor
  • Unfolded protein response

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Endocrinology
  • Pharmacology
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Interplay between steroid hormone activation of the unfolded protein response and nuclear receptor action. / Zheng, Xiaobin; Andruska, Neal; Yu, Liqun; Mao, Chengjian; Kim, Ji Eun; Livezey, Mara; Helferich, William G.; Shapiro, David J.

In: Steroids, Vol. 114, 01.01.2016, p. 2-6.

Research output: Contribution to journalReview article

Zheng, Xiaobin ; Andruska, Neal ; Yu, Liqun ; Mao, Chengjian ; Kim, Ji Eun ; Livezey, Mara ; Helferich, William G. ; Shapiro, David J. / Interplay between steroid hormone activation of the unfolded protein response and nuclear receptor action. In: Steroids. 2016 ; Vol. 114. pp. 2-6.
@article{d9dcd31e5c9d4e1281949fb226583ec9,
title = "Interplay between steroid hormone activation of the unfolded protein response and nuclear receptor action",
abstract = "To identify new pathways of estrogen action and novel estrogen receptor α (ERα) biomodulators, we performed high throughput screening and used follow on assays and bioinformatics to identify small molecule ERα inhibitors with a novel mode of action. These studies led to identification of rapid extranuclear activation of the endoplasmic reticulum stress sensor, the unfolded protein response (UPR), as a new pathway of estrogen-ERα action. Moreover, increasing evidence indicates that the mechanism underlying anticipatory activation of the UPR is shared among steroid and peptide hormones and is conserved from insects to humans. It is likely that this newly unveiled extranuclear pathway is used by diverse mitogenic hormones to prepare cells for the increased protein folding load that will occur during subsequent cell proliferation. Demonstrating biological relevance, elevated expression of a UPR gene signature in ERα positive breast cancer is a powerful new prognostic marker tightly correlated with subsequent resistance to tamoxifen, tumor recurrence and poor survival. In addition, overexpression of epidermal growth factor receptor and HER2/neu is positively correlated with increased UPR activation in breast cancer. This review describes recent research that demonstrates the importance of anticipatory UPR activation in therapy resistant tumors and discusses a promising small molecule biomodulator that inhibits tumor growth by tuning this UPR signaling pathway.",
keywords = "Breast cancer, Cancer, Cell death, Hormone action, Steroid receptor, Unfolded protein response",
author = "Xiaobin Zheng and Neal Andruska and Liqun Yu and Chengjian Mao and Kim, {Ji Eun} and Mara Livezey and Helferich, {William G.} and Shapiro, {David J.}",
year = "2016",
month = "1",
day = "1",
doi = "10.1016/j.steroids.2016.03.014",
language = "English (US)",
volume = "114",
pages = "2--6",
journal = "Steroids",
issn = "0039-128X",
publisher = "Elsevier Inc.",

}

TY - JOUR

T1 - Interplay between steroid hormone activation of the unfolded protein response and nuclear receptor action

AU - Zheng, Xiaobin

AU - Andruska, Neal

AU - Yu, Liqun

AU - Mao, Chengjian

AU - Kim, Ji Eun

AU - Livezey, Mara

AU - Helferich, William G.

AU - Shapiro, David J.

PY - 2016/1/1

Y1 - 2016/1/1

N2 - To identify new pathways of estrogen action and novel estrogen receptor α (ERα) biomodulators, we performed high throughput screening and used follow on assays and bioinformatics to identify small molecule ERα inhibitors with a novel mode of action. These studies led to identification of rapid extranuclear activation of the endoplasmic reticulum stress sensor, the unfolded protein response (UPR), as a new pathway of estrogen-ERα action. Moreover, increasing evidence indicates that the mechanism underlying anticipatory activation of the UPR is shared among steroid and peptide hormones and is conserved from insects to humans. It is likely that this newly unveiled extranuclear pathway is used by diverse mitogenic hormones to prepare cells for the increased protein folding load that will occur during subsequent cell proliferation. Demonstrating biological relevance, elevated expression of a UPR gene signature in ERα positive breast cancer is a powerful new prognostic marker tightly correlated with subsequent resistance to tamoxifen, tumor recurrence and poor survival. In addition, overexpression of epidermal growth factor receptor and HER2/neu is positively correlated with increased UPR activation in breast cancer. This review describes recent research that demonstrates the importance of anticipatory UPR activation in therapy resistant tumors and discusses a promising small molecule biomodulator that inhibits tumor growth by tuning this UPR signaling pathway.

AB - To identify new pathways of estrogen action and novel estrogen receptor α (ERα) biomodulators, we performed high throughput screening and used follow on assays and bioinformatics to identify small molecule ERα inhibitors with a novel mode of action. These studies led to identification of rapid extranuclear activation of the endoplasmic reticulum stress sensor, the unfolded protein response (UPR), as a new pathway of estrogen-ERα action. Moreover, increasing evidence indicates that the mechanism underlying anticipatory activation of the UPR is shared among steroid and peptide hormones and is conserved from insects to humans. It is likely that this newly unveiled extranuclear pathway is used by diverse mitogenic hormones to prepare cells for the increased protein folding load that will occur during subsequent cell proliferation. Demonstrating biological relevance, elevated expression of a UPR gene signature in ERα positive breast cancer is a powerful new prognostic marker tightly correlated with subsequent resistance to tamoxifen, tumor recurrence and poor survival. In addition, overexpression of epidermal growth factor receptor and HER2/neu is positively correlated with increased UPR activation in breast cancer. This review describes recent research that demonstrates the importance of anticipatory UPR activation in therapy resistant tumors and discusses a promising small molecule biomodulator that inhibits tumor growth by tuning this UPR signaling pathway.

KW - Breast cancer

KW - Cancer

KW - Cell death

KW - Hormone action

KW - Steroid receptor

KW - Unfolded protein response

UR - http://www.scopus.com/inward/record.url?scp=84988918092&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84988918092&partnerID=8YFLogxK

U2 - 10.1016/j.steroids.2016.03.014

DO - 10.1016/j.steroids.2016.03.014

M3 - Review article

C2 - 27016130

AN - SCOPUS:84988918092

VL - 114

SP - 2

EP - 6

JO - Steroids

JF - Steroids

SN - 0039-128X

ER -