Estrogen receptor (er)α-regulated lipocalin 2 expression in adipose tissue links obesity with breast cancer progression

Brian G. Drew, Habib Hamidi, Zhenqi Zhou, Claudio J. Villanueva, Susan Miranda, Anna C. Calkin, Brian W. Parks, Vicent Ribas, Nareg Y. Kalajian, Jennifer Phun, Pedram Daraei, Heather R. Christofk, Sylvia C. Hewitt, Kenneth S. Korach, Peter Tontonoz, Aldons J. Lusis, Dennis J. Slamon, Sara A. Hurvitz, Andrea L. Hevener

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Obesity is associated with increased breast cancer (BrCA) incidence. Considering that inactivation of estrogen receptor (ER)α promotes obesity and metabolic dysfunction in women and female mice, understanding the mechanisms and tissuespecific sites of ERα action to combat metabolic-related disease, including BrCA, is of clinical importance. To study the role of ERα in adipose tissue we generated fat-specific ERα knock-out (FERKO) mice. Herein we show that ERα deletion increased adipocyte size, fat pad weight, and tissue expression and circulating levels of the secreted glycoprotein, lipocalin 2 (Lcn2), an adipokine previously associated with BrCA development. Chromatin immunoprecipitation and luciferase reporter studies showed that ERα binds the Lcn2 promoter to repress its expression. Because adipocytes constitute an important cell type of the breast microenvironment, we examined the impact of adipocyte ERα deletion on cancer cell behavior. Conditioned medium from ERα-null adipocytes and medium containing pure Lcn2 increased proliferation and migration of a subset of BrCA cells in culture. The proliferative and promigratory effects of ERα-deficient adipocyte-conditioned medium on BrCA cells was reversed by Lcn2 deletion. BrCA cell responsiveness to exogenous Lcn2 was heightened in cell types where endogenous Lcn2 expression was minimal, but components of the Lcn2 signaling pathway were enriched, i.e. SLC22A17 and 3-hydroxybutyrate dehydrogenase (BDH2). In breast tumor biopsies from women diagnosed with BrCA we found that BDH2 expression was positively associated with adiposity and circulating Lcn2 levels. Collectively these data suggest that reduction of ERα expression in adipose tissue promotes adiposity and is linked with the progression and severity of BrCA via increased adipocyte-specific Lcn2 production and enhanced tumor cell Lcn2 sensitivity.

Original languageEnglish (US)
Pages (from-to)5566-5581
Number of pages16
JournalJournal of Biological Chemistry
Volume290
Issue number9
DOIs
StatePublished - Feb 27 2015

Fingerprint

Lipocalins
Estrogen Receptors
Adipose Tissue
Obesity
Tissue
Breast Neoplasms
Adipocytes
Adiposity
Conditioned Culture Medium
Tumors
Hydroxybutyrate Dehydrogenase
Fats
Cells
Lipocalin-2
Cellular Microenvironment
Adipokines
Biopsy
Chromatin Immunoprecipitation
Metabolic Diseases
Luciferases

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Estrogen receptor (er)α-regulated lipocalin 2 expression in adipose tissue links obesity with breast cancer progression. / Drew, Brian G.; Hamidi, Habib; Zhou, Zhenqi; Villanueva, Claudio J.; Miranda, Susan; Calkin, Anna C.; Parks, Brian W.; Ribas, Vicent; Kalajian, Nareg Y.; Phun, Jennifer; Daraei, Pedram; Christofk, Heather R.; Hewitt, Sylvia C.; Korach, Kenneth S.; Tontonoz, Peter; Lusis, Aldons J.; Slamon, Dennis J.; Hurvitz, Sara A.; Hevener, Andrea L.

In: Journal of Biological Chemistry, Vol. 290, No. 9, 27.02.2015, p. 5566-5581.

Research output: Contribution to journalArticle

Drew, BG, Hamidi, H, Zhou, Z, Villanueva, CJ, Miranda, S, Calkin, AC, Parks, BW, Ribas, V, Kalajian, NY, Phun, J, Daraei, P, Christofk, HR, Hewitt, SC, Korach, KS, Tontonoz, P, Lusis, AJ, Slamon, DJ, Hurvitz, SA & Hevener, AL 2015, 'Estrogen receptor (er)α-regulated lipocalin 2 expression in adipose tissue links obesity with breast cancer progression', Journal of Biological Chemistry, vol. 290, no. 9, pp. 5566-5581. https://doi.org/10.1074/jbc.M114.606459
Drew, Brian G. ; Hamidi, Habib ; Zhou, Zhenqi ; Villanueva, Claudio J. ; Miranda, Susan ; Calkin, Anna C. ; Parks, Brian W. ; Ribas, Vicent ; Kalajian, Nareg Y. ; Phun, Jennifer ; Daraei, Pedram ; Christofk, Heather R. ; Hewitt, Sylvia C. ; Korach, Kenneth S. ; Tontonoz, Peter ; Lusis, Aldons J. ; Slamon, Dennis J. ; Hurvitz, Sara A. ; Hevener, Andrea L. / Estrogen receptor (er)α-regulated lipocalin 2 expression in adipose tissue links obesity with breast cancer progression. In: Journal of Biological Chemistry. 2015 ; Vol. 290, No. 9. pp. 5566-5581.
@article{8b655396426747759e423648fb3958a1,
title = "Estrogen receptor (er)α-regulated lipocalin 2 expression in adipose tissue links obesity with breast cancer progression",
abstract = "Obesity is associated with increased breast cancer (BrCA) incidence. Considering that inactivation of estrogen receptor (ER)α promotes obesity and metabolic dysfunction in women and female mice, understanding the mechanisms and tissuespecific sites of ERα action to combat metabolic-related disease, including BrCA, is of clinical importance. To study the role of ERα in adipose tissue we generated fat-specific ERα knock-out (FERKO) mice. Herein we show that ERα deletion increased adipocyte size, fat pad weight, and tissue expression and circulating levels of the secreted glycoprotein, lipocalin 2 (Lcn2), an adipokine previously associated with BrCA development. Chromatin immunoprecipitation and luciferase reporter studies showed that ERα binds the Lcn2 promoter to repress its expression. Because adipocytes constitute an important cell type of the breast microenvironment, we examined the impact of adipocyte ERα deletion on cancer cell behavior. Conditioned medium from ERα-null adipocytes and medium containing pure Lcn2 increased proliferation and migration of a subset of BrCA cells in culture. The proliferative and promigratory effects of ERα-deficient adipocyte-conditioned medium on BrCA cells was reversed by Lcn2 deletion. BrCA cell responsiveness to exogenous Lcn2 was heightened in cell types where endogenous Lcn2 expression was minimal, but components of the Lcn2 signaling pathway were enriched, i.e. SLC22A17 and 3-hydroxybutyrate dehydrogenase (BDH2). In breast tumor biopsies from women diagnosed with BrCA we found that BDH2 expression was positively associated with adiposity and circulating Lcn2 levels. Collectively these data suggest that reduction of ERα expression in adipose tissue promotes adiposity and is linked with the progression and severity of BrCA via increased adipocyte-specific Lcn2 production and enhanced tumor cell Lcn2 sensitivity.",
author = "Drew, {Brian G.} and Habib Hamidi and Zhenqi Zhou and Villanueva, {Claudio J.} and Susan Miranda and Calkin, {Anna C.} and Parks, {Brian W.} and Vicent Ribas and Kalajian, {Nareg Y.} and Jennifer Phun and Pedram Daraei and Christofk, {Heather R.} and Hewitt, {Sylvia C.} and Korach, {Kenneth S.} and Peter Tontonoz and Lusis, {Aldons J.} and Slamon, {Dennis J.} and Hurvitz, {Sara A.} and Hevener, {Andrea L.}",
year = "2015",
month = "2",
day = "27",
doi = "10.1074/jbc.M114.606459",
language = "English (US)",
volume = "290",
pages = "5566--5581",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "9",

}

TY - JOUR

T1 - Estrogen receptor (er)α-regulated lipocalin 2 expression in adipose tissue links obesity with breast cancer progression

AU - Drew, Brian G.

AU - Hamidi, Habib

AU - Zhou, Zhenqi

AU - Villanueva, Claudio J.

AU - Miranda, Susan

AU - Calkin, Anna C.

AU - Parks, Brian W.

AU - Ribas, Vicent

AU - Kalajian, Nareg Y.

AU - Phun, Jennifer

AU - Daraei, Pedram

AU - Christofk, Heather R.

AU - Hewitt, Sylvia C.

AU - Korach, Kenneth S.

AU - Tontonoz, Peter

AU - Lusis, Aldons J.

AU - Slamon, Dennis J.

AU - Hurvitz, Sara A.

AU - Hevener, Andrea L.

PY - 2015/2/27

Y1 - 2015/2/27

N2 - Obesity is associated with increased breast cancer (BrCA) incidence. Considering that inactivation of estrogen receptor (ER)α promotes obesity and metabolic dysfunction in women and female mice, understanding the mechanisms and tissuespecific sites of ERα action to combat metabolic-related disease, including BrCA, is of clinical importance. To study the role of ERα in adipose tissue we generated fat-specific ERα knock-out (FERKO) mice. Herein we show that ERα deletion increased adipocyte size, fat pad weight, and tissue expression and circulating levels of the secreted glycoprotein, lipocalin 2 (Lcn2), an adipokine previously associated with BrCA development. Chromatin immunoprecipitation and luciferase reporter studies showed that ERα binds the Lcn2 promoter to repress its expression. Because adipocytes constitute an important cell type of the breast microenvironment, we examined the impact of adipocyte ERα deletion on cancer cell behavior. Conditioned medium from ERα-null adipocytes and medium containing pure Lcn2 increased proliferation and migration of a subset of BrCA cells in culture. The proliferative and promigratory effects of ERα-deficient adipocyte-conditioned medium on BrCA cells was reversed by Lcn2 deletion. BrCA cell responsiveness to exogenous Lcn2 was heightened in cell types where endogenous Lcn2 expression was minimal, but components of the Lcn2 signaling pathway were enriched, i.e. SLC22A17 and 3-hydroxybutyrate dehydrogenase (BDH2). In breast tumor biopsies from women diagnosed with BrCA we found that BDH2 expression was positively associated with adiposity and circulating Lcn2 levels. Collectively these data suggest that reduction of ERα expression in adipose tissue promotes adiposity and is linked with the progression and severity of BrCA via increased adipocyte-specific Lcn2 production and enhanced tumor cell Lcn2 sensitivity.

AB - Obesity is associated with increased breast cancer (BrCA) incidence. Considering that inactivation of estrogen receptor (ER)α promotes obesity and metabolic dysfunction in women and female mice, understanding the mechanisms and tissuespecific sites of ERα action to combat metabolic-related disease, including BrCA, is of clinical importance. To study the role of ERα in adipose tissue we generated fat-specific ERα knock-out (FERKO) mice. Herein we show that ERα deletion increased adipocyte size, fat pad weight, and tissue expression and circulating levels of the secreted glycoprotein, lipocalin 2 (Lcn2), an adipokine previously associated with BrCA development. Chromatin immunoprecipitation and luciferase reporter studies showed that ERα binds the Lcn2 promoter to repress its expression. Because adipocytes constitute an important cell type of the breast microenvironment, we examined the impact of adipocyte ERα deletion on cancer cell behavior. Conditioned medium from ERα-null adipocytes and medium containing pure Lcn2 increased proliferation and migration of a subset of BrCA cells in culture. The proliferative and promigratory effects of ERα-deficient adipocyte-conditioned medium on BrCA cells was reversed by Lcn2 deletion. BrCA cell responsiveness to exogenous Lcn2 was heightened in cell types where endogenous Lcn2 expression was minimal, but components of the Lcn2 signaling pathway were enriched, i.e. SLC22A17 and 3-hydroxybutyrate dehydrogenase (BDH2). In breast tumor biopsies from women diagnosed with BrCA we found that BDH2 expression was positively associated with adiposity and circulating Lcn2 levels. Collectively these data suggest that reduction of ERα expression in adipose tissue promotes adiposity and is linked with the progression and severity of BrCA via increased adipocyte-specific Lcn2 production and enhanced tumor cell Lcn2 sensitivity.

UR - http://www.scopus.com/inward/record.url?scp=84923872915&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84923872915&partnerID=8YFLogxK

U2 - 10.1074/jbc.M114.606459

DO - 10.1074/jbc.M114.606459

M3 - Article

VL - 290

SP - 5566

EP - 5581

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 9

ER -