Home LiteratureArticle Details
PMID: 22995915 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Stromal adipocyte enhancer-binding protein (AEBP1) promotes mammary epithelial cell hyperplasia via proinflammatory and hedgehog signaling.

The Journal of biological chemistry ·Vol. 287 ·No. 46 ·2012-11-09 ·Pages 39171-81

Holloway RW, Bogachev O, Bharadwaj AG, McCluskey GD, Majdalawieh AF, Zhang L, Ro HS

Abstract

Disruption of mammary stromal-epithelial communication leads to aberrant mammary gland development and induces mammary tumorigenesis. Macrophages have been implicated in carcinogenesis primarily by creating an inflammatory microenvironment, which promotes growth of the adjacent epithelial cells. Adipocyte enhancer-binding protein 1 (AEBP1), a novel proinflammatory mediator, promotes macrophage inflammatory responsiveness by inducing NF-κB activity, which has been implicated in tumor cell growth and survival by aberrant sonic hedgehog (Shh) expression. Here, we show that stromal macrophage AEBP1 overexpression results in precocious alveologenesis in the virgin AEBP1 transgenic (AEBP1(TG)) mice, and the onset of ductal hyperplasia was accelerated in AEBP1(TG) mice fed a high fat diet, which induces endogenous AEBP1 expression. Transplantation of AEBP1(TG) bone marrow cells into non-transgenic (AEBP1(NT)) mice resulted in alveolar hyperplasia with up-regulation of NF-κB activity and TNFα expression as displayed in the AEBP1(TG) mammary macrophages and epithelium. Shh expression was induced in AEBP1(TG) macrophages and RAW264.7 macrophages overexpressing AEBP1. The Shh target genes Gli1 and Bmi1 expression was induced in the AEBP1(TG) mammary epithelium and HC11 mammary epithelial cells co-cultured with AEBP1(TG) peritoneal macrophages. The conditioned AEBP1(TG) macrophage culture media promoted NF-κB activity and survival signal, Akt activation, in HC11 cells, whereas such effects were abolished by TNFα neutralizing antibody treatment. Furthermore, HC11 cells displayed enhanced proliferation in response to AEBP1(TG) macrophages and their conditioned media. Our findings highlight the role of AEBP1 in the signaling pathways regulating the cross-talk between mammary epithelium and stroma that could predispose the mammary tissue to tumorigenesis.

MeSH Terms
Animals Bone Marrow Transplantation Carboxypeptidases/genetics,physiology Cell Line Coculture Techniques Culture Media, Conditioned/pharmacology Hedgehog Proteins/metabolism Hyperplasia Inflammation Macrophages/metabolism Mammary Glands, Animal/metabolism,pathology Mice Mice, Transgenic NF-kappa B/metabolism Repressor Proteins/genetics,physiology Signal Transduction Tumor Necrosis Factor-alpha/metabolism
Chemicals
Aebp1 protein, mouse Culture Media, Conditioned Hedgehog Proteins NF-kappa B Repressor Proteins Shh protein, mouse Tumor Necrosis Factor-alpha Carboxypeptidases
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Holloway Ryan W
Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, Nova Scotia, B3H 1X5, Canada.
Bogachev Oleg
Bharadwaj Alamelu G
McCluskey Greg D
Majdalawieh Amin F
Zhang Lei
Ro Hyo-Sung
References (49)
49 references, click to expand
  1. Establishment of the epithelial-specific transcriptome of normal and malignant human breast cells based on MPSS and array expression data.
    Breast Cancer Res. 2006;8(5):R56 PMID: 17014703
  2. Inflammatory mediators in breast cancer: coordinated expression of TNFα & IL-1β with CCL2 & CCL5 and effects on epithelial-to-mesenchymal transition.
    BMC Cancer. 2011 Apr 12;11:130 PMID: 21486440
  3. The Hedgehog and Wnt signalling pathways in cancer.
    Nature. 2001 May 17;411(6835):349-54 PMID: 11357142
  4. Snail induction is an early response to Gli1 that determines the efficiency of epithelial transformation.
    Oncogene. 2006 Jan 26;25(4):609-21 PMID: 16158046
  5. Stromal effects on mammary gland development and breast cancer.
    Science. 2002 May 10;296(5570):1046-9 PMID: 12004111
  6. Inflammation and IGF-I activate the Akt pathway in breast cancer.
    Int J Cancer. 2007 Feb 15;120(4):796-805 PMID: 17096325
  7. Prostatic intraepithelial neoplasia and adenocarcinoma in mice expressing a probasin-Neu oncogenic transgene.
    Carcinogenesis. 2006 May;27(5):1054-67 PMID: 16401639
  8. Signal transduction by tumor necrosis factor and its relatives.
    Trends Cell Biol. 2001 Sep;11(9):372-7 PMID: 11514191
  9. Nuclear factor-kappaB contributes to hedgehog signaling pathway activation through sonic hedgehog induction in pancreatic cancer.
    Cancer Res. 2006 Jul 15;66(14):7041-9 PMID: 16849549
  10. Progression of mouse mammary tumors: MCP-1-TNFalpha cross-regulatory pathway and clonal expression of promalignancy and antimalignancy factors.
    Int J Cancer. 2003 Oct 10;106(6):879-86 PMID: 12918065
  11. Characterization of sonic hedgehog as a novel NF-kappaB target gene that promotes NF-kappaB-mediated apoptosis resistance and tumor growth in vivo.
    FASEB J. 2009 Jan;23(1):21-33 PMID: 18772349
  12. PPARgamma1 and LXRalpha face a new regulator of macrophage cholesterol homeostasis and inflammatory responsiveness, AEBP1.
    Nucl Recept Signal. 2010 Apr 16;8:e004 PMID: 20419060
  13. Novel glioblastoma markers with diagnostic and prognostic value identified through transcriptome analysis.
    Clin Cancer Res. 2008 May 15;14(10):2978-87 PMID: 18483363
  14. At the crossroads of inflammation and cancer.
    Cell. 2004 Sep 17;118(6):671-4 PMID: 15369667
  15. Regulation of adipogenesis by a transcriptional repressor that modulates MAPK activation.
    J Biol Chem. 2001 Mar 30;276(13):10199-206 PMID: 11152475
  16. Inhibition of sonic hedgehog autoprocessing in cultured mammalian cells by sterol deprivation.
    Proc Natl Acad Sci U S A. 2000 Jun 20;97(13):7307-12 PMID: 10860995
  17. Lactation defect with impaired secretory activation in AEBP1-null mice.
    PLoS One. 2011;6(11):e27795 PMID: 22114697
  18. Adipocyte enhancer-binding protein-1 promotes macrophage inflammatory responsiveness by up-regulating NF-kappaB via IkappaBalpha negative regulation.
    Mol Biol Cell. 2007 Mar;18(3):930-42 PMID: 17202411
  19. Several distinct polycomb complexes regulate and co-localize on the INK4a tumor suppressor locus.
    PLoS One. 2009 Jul 28;4(7):e6380 PMID: 19636380
  20. Is NF-kappaB a good target for cancer therapy? Hopes and pitfalls.
    Nat Rev Drug Discov. 2009 Jan;8(1):33-40 PMID: 19116625
  21. Gene structure and expression of the mouse adipocyte enhancer-binding protein.
    Gene. 2001 Dec 12;280(1-2):123-33 PMID: 11738825
  22. Expression and regulation mechanisms of Sonic Hedgehog in breast cancer.
    Cancer Sci. 2010 Apr;101(4):927-33 PMID: 20180807
  23. Hedgehog regulates cell growth and proliferation by inducing Cyclin D and Cyclin E.
    Nature. 2002 May 16;417(6886):299-304 PMID: 12015606
  24. A stroma-related gene signature predicts resistance to neoadjuvant chemotherapy in breast cancer.
    Nat Med. 2009 Jan;15(1):68-74 PMID: 19122658
  25. Transcriptional regulation of bcl-2 mediated by the sonic hedgehog signaling pathway through gli-1.
    J Biol Chem. 2004 Jan 9;279(2):1197-205 PMID: 14555646
  26. Mammary gland macrophages: pleiotropic functions in mammary development.
    J Mammary Gland Biol Neoplasia. 2006 Oct;11(3-4):229-38 PMID: 17115264
  27. The role of AEBP1 in sex-specific diet-induced obesity.
    Mol Med. 2005 Jan-Dec;11(1-12):39-47 PMID: 16307171
  28. Hedgehog signaling promotes prostate xenograft tumor growth.
    Endocrinology. 2004 Aug;145(8):3961-70 PMID: 15132968
  29. Sonic hedgehog pathway promotes metastasis and lymphangiogenesis via activation of Akt, EMT, and MMP-9 pathway in gastric cancer.
    Cancer Res. 2011 Nov 15;71(22):7061-70 PMID: 21975935
  30. The morphogen Sonic hedgehog is an indirect angiogenic agent upregulating two families of angiogenic growth factors.
    Nat Med. 2001 Jun;7(6):706-11 PMID: 11385508
  31. Adipocyte enhancer-binding protein 1 (AEBP1) (a novel macrophage proinflammatory mediator) overexpression promotes and ablation attenuates atherosclerosis in ApoE (-/-) and LDLR (-/-) mice.
    Mol Med. 2011 Sep-Oct;17(9-10):1056-64 PMID: 21687917
  32. Adipocyte enhancer-binding protein 1 modulates adiposity and energy homeostasis.
    Obesity (Silver Spring). 2007 Feb;15(2):288-302 PMID: 17299101
  33. LPS-induced suppression of macrophage cholesterol efflux is mediated by adipocyte enhancer-binding protein 1.
    Int J Biochem Cell Biol. 2009 Jul;41(7):1518-25 PMID: 19166963
  34. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis.
    Nature. 2011 Jun 08;475(7355):222-5 PMID: 21654748
  35. Missing pieces in the NF-kappaB puzzle.
    Cell. 2002 Apr;109 Suppl:S81-96 PMID: 11983155
  36. Inflammation and cancer.
    Nature. 2002 Dec 19-26;420(6917):860-7 PMID: 12490959
  37. Adipocyte enhancer-binding protein 1 is a potential novel atherogenic factor involved in macrophage cholesterol homeostasis and inflammation.
    Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2346-51 PMID: 16461908
  38. The works of GLI and the power of hedgehog.
    Nat Cell Biol. 1999 Oct;1(6):E147-8 PMID: 10559974
  39. Nuclear factor-kappaB in cancer development and progression.
    Nature. 2006 May 25;441(7092):431-6 PMID: 16724054
  40. Phosphoinositide 3-kinase and Akt are essential for Sonic Hedgehog signaling.
    Proc Natl Acad Sci U S A. 2006 Mar 21;103(12):4505-10 PMID: 16537363
  41. Sonic hedgehog regulates Bmi1 in human medulloblastoma brain tumor-initiating cells.
    Oncogene. 2012 Jan 12;31(2):187-99 PMID: 21685941
  42. Identification of signal transduction pathways involved in constitutive NF-kappaB activation in breast cancer cells.
    Oncogene. 2002 Mar 27;21(13):2066-78 PMID: 11960379
  43. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method.
    Methods. 2001 Dec;25(4):402-8 PMID: 11846609
  44. Negative regulation of Hedgehog signaling by liver X receptors.
    Mol Endocrinol. 2009 Oct;23(10):1532-43 PMID: 19608643
  45. Tumor necrosis factor deficiency inhibits mammary tumorigenesis and a tumor necrosis factor neutralizing antibody decreases mammary tumor growth in neu/erbB2 transgenic mice.
    Mol Cancer Ther. 2009 Sep;8(9):2655-63 PMID: 19755514
  46. Regulation of IkappaBalpha function and NF-kappaB signaling: AEBP1 is a novel proinflammatory mediator in macrophages.
    Mediators Inflamm. 2010;2010:823821 PMID: 20396415
  47. Hedgehog signaling in animal development: paradigms and principles.
    Genes Dev. 2001 Dec 1;15(23):3059-87 PMID: 11731473
  48. Nuclear factor kappaB-activated monocytes contribute to pancreatic cancer progression through the production of Shh.
    Cancer Immunol Immunother. 2010 May;59(5):675-86 PMID: 19862523
  49. Shared principles in NF-kappaB signaling.
    Cell. 2008 Feb 8;132(3):344-62 PMID: 18267068
Article Info
Journal
The Journal of biological chemistry
Abbr.
J Biol Chem
ISSN
1083-351X
DOI
10.1074/jbc.M112.404293
Published
2012-11-09
Epub
2012-00-20
Pages
39171-81
Language
English
Region
United States
NLM ID
2985121R
PMCID
PMC3493957
Subset
IM
Grants
Canadian Institutes of Health Research · MOP-57675 · Canada
External Links
PubMed source DOI: 10.1074/jbc.M112.404293 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2