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J Biol Chem. 2015 Feb 27;290(9):5566-81. doi: 10.1074/jbc.M114.606459. Epub 2014 Dec 2.

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

Author information

1
From the David Geffen School of Medicine, Department of Medicine, Division of Endocrinology, Diabetes and Hypertension.
2
Division of Hematology-Oncology, and Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California 90095.
3
the Department of Pathology and Laboratory Medicine, Howard Hughes Medical Institute, UCLA, Los Angeles, California 90095.
4
the Orthopaedic Hospital Department of Orthopaedic Surgery and the Orthopaedic Hospital Research Center, UCLA, Los Angeles, California 90095.
5
the Departments of Human Genetics and.
6
Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California 90095, Molecular and Medical Pharmacology, UCLA, Los Angeles, California 90095.
7
the Receptor Biology Section, Reproductive and Developmental Biology Laboratory, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709, and.
8
Division of Hematology-Oncology, and Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California 90095, the Translational Research in Oncology-US.
9
From the David Geffen School of Medicine, Department of Medicine, Division of Endocrinology, Diabetes and Hypertension, Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California 90095, Iris Cantor-UCLA Women's Health Center, Los Angeles, California 90095 ahevener@mednet.ucla.edu.

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 tissue-specific 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.

KEYWORDS:

Adipokine; Breast Cancer; Estrogen Receptor; Iron Metabolism; Obesity

PMID:
25468909
PMCID:
PMC4342471
DOI:
10.1074/jbc.M114.606459
[Indexed for MEDLINE]
Free PMC Article

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