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 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.
authors.affiliation: From the David Geffen School of Medicine, Department of Medicine, Division of Endocrinology, Diabetes and Hypertension.
authors.forename: Brian G
authors.initials: BG
authors.lastname: Drew
authors.affiliation: Division of Hematology-Oncology, and Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California 90095.
authors.forename: Habib
authors.initials: H
authors.lastname: Hamidi
authors.affiliation: From the David Geffen School of Medicine, Department of Medicine, Division of Endocrinology, Diabetes and Hypertension.
authors.forename: Zhenqi
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: the Department of Pathology and Laboratory Medicine, Howard Hughes Medical Institute, UCLA, Los Angeles, California 90095.
authors.forename: Claudio J
authors.initials: CJ
authors.lastname: Villanueva
authors.affiliation: the Orthopaedic Hospital Department of Orthopaedic Surgery and the Orthopaedic Hospital Research Center, UCLA, Los Angeles, California 90095.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Krum
authors.affiliation: the Department of Pathology and Laboratory Medicine, Howard Hughes Medical Institute, UCLA, Los Angeles, California 90095.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Calkin
authors.affiliation: the Departments of Human Genetics and.
authors.forename: Brian W
authors.initials: BW
authors.lastname: Parks
authors.affiliation: From the David Geffen School of Medicine, Department of Medicine, Division of Endocrinology, Diabetes and Hypertension.
authors.forename: Vicent
authors.initials: V
authors.lastname: Ribas
authors.affiliation: From the David Geffen School of Medicine, Department of Medicine, Division of Endocrinology, Diabetes and Hypertension.
authors.forename: Nareg Y
authors.initials: NY
authors.lastname: Kalajian
authors.affiliation: From the David Geffen School of Medicine, Department of Medicine, Division of Endocrinology, Diabetes and Hypertension.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Phun
authors.affiliation: From the David Geffen School of Medicine, Department of Medicine, Division of Endocrinology, Diabetes and Hypertension.
authors.forename: Pedram
authors.initials: P
authors.lastname: Daraei
authors.affiliation: Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California 90095, Molecular and Medical Pharmacology, UCLA, Los Angeles, California 90095.
authors.forename: Heather R
authors.initials: HR
authors.lastname: Christofk
authors.affiliation: the Receptor Biology Section, Reproductive and Developmental Biology Laboratory, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709, and.
authors.forename: Sylvia C
authors.initials: SC
authors.lastname: Hewitt
authors.affiliation: the Receptor Biology Section, Reproductive and Developmental Biology Laboratory, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709, and.
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Korach
authors.affiliation: the Department of Pathology and Laboratory Medicine, Howard Hughes Medical Institute, UCLA, Los Angeles, California 90095.
authors.forename: Peter
authors.initials: P
authors.lastname: Tontonoz
authors.affiliation: the Departments of Human Genetics and.
authors.forename: Aldons J
authors.initials: AJ
authors.lastname: Lusis
authors.affiliation: Division of Hematology-Oncology, and Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California 90095, the Translational Research in Oncology-US.
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Slamon
authors.affiliation: Division of Hematology-Oncology, and Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California 90095, the Translational Research in Oncology-US.
authors.forename: Sara A
authors.initials: SA
authors.lastname: Hurvitz
authors.affiliation: 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.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Hevener
mesh_terms: D041721:3T3-L1 Cells; D000209:Acute-Phase Proteins / Q000235:genetics / Q000378:metabolism*; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D018450:Disease Progression; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D000071068:Lipocalin-2; D054834:Lipocalins / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D015513:Oncogene Proteins / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000209:Acute-Phase Proteins; D047628:Estrogen Receptor alpha; D000071068:Lipocalin-2; D054834:Lipocalins; D015513:Oncogene Proteins; C071332:Lcn2 protein, mouse
keywords: Adipokine; Breast Cancer; Estrogen Receptor; Iron Metabolism; Obesity