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

Brian Gary Drew, Habib Hamidi, Zhenqi Zhou, Claudio J Villanueva, Susan A Krum, Anna Calkin, Brian Wesley Parks, Vicent Ribas, Nareg Y Kalajian, Jennifer Phun, Pedram Daraei, Heather Renee Christofk, Sylvia Curtis Hewitt, Kenneth S Korach, Peter Tontonoz, Aldons Jake Lusis, Dennis J Slamon, Sara A Hurvitz, Andrea Hevener

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Obesity is associated with increased breast cancer (BrCA) incidence. Considering that inactivation of estrogen receptor (ER)a promotes obesity and metabolic dysfunction in women and female mice, understanding the mechanisms and tissuespecific sites of ERa action to combat metabolic-related disease, including BrCA, is of clinical importance. To study the role of ERa in adipose tissue we generated fat-specific ERa knock-out (FERKO) mice. Herein we show that ERa 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 ERa 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 ERa deletion on cancer cell behavior. Conditioned medium from ERa-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 ERa-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 ERa 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
Pages (from-to)5566 - 5581
Number of pages16
JournalJournal of Biological Chemistry
Volume290
Issue number9
DOIs
Publication statusPublished - 2015

Cite this

Drew, Brian Gary ; Hamidi, Habib ; Zhou, Zhenqi ; Villanueva, Claudio J ; Krum, Susan A ; Calkin, Anna ; Parks, Brian Wesley ; Ribas, Vicent ; Kalajian, Nareg Y ; Phun, Jennifer ; Daraei, Pedram ; Christofk, Heather Renee ; Hewitt, Sylvia Curtis ; Korach, Kenneth S ; Tontonoz, Peter ; Lusis, Aldons Jake ; Slamon, Dennis J ; Hurvitz, Sara A ; Hevener, Andrea. / Estrogen receptor (ER)alpha-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.
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title = "Estrogen receptor (ER)alpha-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)a promotes obesity and metabolic dysfunction in women and female mice, understanding the mechanisms and tissuespecific sites of ERa action to combat metabolic-related disease, including BrCA, is of clinical importance. To study the role of ERa in adipose tissue we generated fat-specific ERa knock-out (FERKO) mice. Herein we show that ERa 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 ERa 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 ERa deletion on cancer cell behavior. Conditioned medium from ERa-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 ERa-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 ERa 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 Gary} and Habib Hamidi and Zhenqi Zhou and Villanueva, {Claudio J} and Krum, {Susan A} and Anna Calkin and Parks, {Brian Wesley} and Vicent Ribas and Kalajian, {Nareg Y} and Jennifer Phun and Pedram Daraei and Christofk, {Heather Renee} and Hewitt, {Sylvia Curtis} and Korach, {Kenneth S} and Peter Tontonoz and Lusis, {Aldons Jake} and Slamon, {Dennis J} and Hurvitz, {Sara A} and Andrea Hevener",
year = "2015",
doi = "10.1074/jbc.M114.606459",
language = "English",
volume = "290",
pages = "5566 -- 5581",
journal = "Journal of Biological Chemistry",
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Drew, BG, Hamidi, H, Zhou, Z, Villanueva, CJ, Krum, SA, Calkin, A, 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, A 2015, 'Estrogen receptor (ER)alpha-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

Estrogen receptor (ER)alpha-regulated lipocalin 2 expression in adipose tissue links obesity with breast cancer progression. / Drew, Brian Gary; Hamidi, Habib; Zhou, Zhenqi; Villanueva, Claudio J; Krum, Susan A; Calkin, Anna; Parks, Brian Wesley; Ribas, Vicent; Kalajian, Nareg Y; Phun, Jennifer; Daraei, Pedram; Christofk, Heather Renee; Hewitt, Sylvia Curtis; Korach, Kenneth S; Tontonoz, Peter; Lusis, Aldons Jake; Slamon, Dennis J; Hurvitz, Sara A; Hevener, Andrea.

In: Journal of Biological Chemistry, Vol. 290, No. 9, 2015, p. 5566 - 5581.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

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

AU - Drew, Brian Gary

AU - Hamidi, Habib

AU - Zhou, Zhenqi

AU - Villanueva, Claudio J

AU - Krum, Susan A

AU - Calkin, Anna

AU - Parks, Brian Wesley

AU - Ribas, Vicent

AU - Kalajian, Nareg Y

AU - Phun, Jennifer

AU - Daraei, Pedram

AU - Christofk, Heather Renee

AU - Hewitt, Sylvia Curtis

AU - Korach, Kenneth S

AU - Tontonoz, Peter

AU - Lusis, Aldons Jake

AU - Slamon, Dennis J

AU - Hurvitz, Sara A

AU - Hevener, Andrea

PY - 2015

Y1 - 2015

N2 - Obesity is associated with increased breast cancer (BrCA) incidence. Considering that inactivation of estrogen receptor (ER)a promotes obesity and metabolic dysfunction in women and female mice, understanding the mechanisms and tissuespecific sites of ERa action to combat metabolic-related disease, including BrCA, is of clinical importance. To study the role of ERa in adipose tissue we generated fat-specific ERa knock-out (FERKO) mice. Herein we show that ERa 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 ERa 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 ERa deletion on cancer cell behavior. Conditioned medium from ERa-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 ERa-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 ERa 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)a promotes obesity and metabolic dysfunction in women and female mice, understanding the mechanisms and tissuespecific sites of ERa action to combat metabolic-related disease, including BrCA, is of clinical importance. To study the role of ERa in adipose tissue we generated fat-specific ERa knock-out (FERKO) mice. Herein we show that ERa 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 ERa 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 ERa deletion on cancer cell behavior. Conditioned medium from ERa-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 ERa-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 ERa 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.jbc.org/content/290/9/5566.full.pdf+html

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 - 1083-351X

IS - 9

ER -