Elsevier

Pharmacological Research

Volume 119, May 2017, Pages 278-288
Pharmacological Research

Invited Review-pharmacology across disciplines
Annexin A1 influences in breast cancer: Controversies on contributions to tumour, host and immunoediting processes

https://doi.org/10.1016/j.phrs.2017.02.011Get rights and content

Abstract

Annexin A1 is a multifunctional protein characterised by its actions in modulating the innate and adaptive immune response. Accumulating evidence of altered annexin A1 expression in many human tumours raises interest in its functional role in cancer biology. In breast cancer, altered annexin A1 expression levels suggest a potential influence on tumorigenic and metastatic processes. However, reports of conflicting results reveal a relationship that is much more complex than first conceptualised. In this review, we explore the diverse actions of annexin A1 on breast tumour cells and various host cell types, including stromal immune and structural cells, particularly in the context of cancer immunoediting.

Section snippets

Background

Annexin A1 (gene symbol ANXA1) is the first characterised member of the Annexin family, so named for their property of binding or “annexing” to phospholipid membranes in a calcium-dependent manner [1]. The annexin family comprises 13 structurally and biologically related proteins having in common a core domain containing four similar repeats (except for annexin A6) and a unique N-terminal region that confers subtype specific biological activity [2], [3]. The N-terminal region is exposed in the

Heterogeneous expression of Annexin A1 in breast cancer progression

Interest in the functional role of annexin A1 in cancer biology arises from accumulating evidence of altered expression in human solid tumours and blood cancers (reviewed by [39], [40], [41]). In human breast cancer (BC), expression of annexin A1 is also altered. Unlike in most other tumours, the large number of reports of annexin A1 expression pattern in human breast cancer revealed seemingly contradictory results that are discussed in detail below (Table 1).

Influence of Annexin A1 on breast cancer cell migration, proliferation and EMT

The controversy regarding the expression pattern of annexin A1 in breast cancer is paralleled by the largely varied in vitro findings amongst the literature investigating the influence of annexin A1 on breast cancer cell behaviour. In these studies, intracellular annexin A1 levels were either reduced or elevated to deduce a relationship associated with tumour cell behaviour including migration, proliferation, invasion and epithelial–mesenchymal transition (EMT) (Table 2).

Host annexin A1: potential involvement in immunoediting

The importance of the immune system in the development of human tumours has been long established. However, whether the immune system has positive or negative effects on tumour development and progression has been debated for the last two decades. With the accumulation of clinical and experimental data, we now understand that the immune system has the capacity to both protect the host from cancer and to promote cancer growth and spread, termed cancer immunoediting. Given the importance of

Implications and future directions

In this article, we reviewed the current understanding of the influence of annexin A1 in breast cancer development and progression. We discussed evidence that annexin A1 exhibits dualistic, temporally and spatially dynamic actions on different cell types within a tumour. We discussed, for the first time, a potential role for annexin A1 in cancer immunoediting. The complex biology of annexin A1 and the heterogeneous nature of breast cancer makes the deciphering the influence of this protein on

Acknowledgment

The authors’ work cited in this review was supported by a grant from NHMRC#1023185.

References (145)

  • E.F. Morand et al.

    Detection of intracellular lipocortin 1 in human leukocyte subsets

    Clin. Immunol. Immunopathol.

    (1995)
  • L. Spurr et al.

    Comparative analysis of Annexin A1-formyl peptide receptor 2/ALX expression in human leukocyte subsets

    Int. Immunopharmacol.

    (2011)
  • F. D’Acquisto

    On the adaptive nature of annexin-A1

    Curr. Opin. Pharmacol.

    (2009)
  • C. Ho-Yen et al.

    Characterization of basal-like breast cancer: an update

    Diagn. Histopathol.

    (2012)
  • D.J. Shen et al.

    Decreased expression of annexin A1 is correlated with breast cancer development and progression as determined by a tissue microarray analysis

    Hum. Pathol.

    (2006)
  • P. Bist et al.

    Annexin-A1 controls an ERK-RhoA-NFkappaB activation loop in breast cancer cells

    Biochem. Biophys. Res. Commun.

    (2015)
  • H. Kang et al.

    The role of annexin A1 in expression of matrix metalloproteinase-9 and invasion of breast cancer cells

    Biochem. Biophys. Res. Commun.

    (2012)
  • D. Hanahan et al.

    Hallmarks of cancer: the next generation

    Cell

    (2011)
  • Y. Su et al.

    Somatic cell fusions reveal extensive heterogeneity in basal-like Breast cancer

    Cell Rep.

    (2015)
  • D. Mittal et al.

    New insights into cancer immunoediting and its three component phases-elimination, equilibrium and escape

    Curr. Opin. Immunol.

    (2014)
  • A. Sica et al.

    Macrophage polarization in tumour progression

    Semin. Cancer Biol.

    (2008)
  • V. Gerke et al.

    Annexins: from structure to function

    Physiol. Rev.

    (2002)
  • V. Gerke et al.

    Annexins: linking Ca2+ signalling to membrane dynamics

    Nat. Rev. Mol. Cell Biol.

    (2005)
  • M. Perretti et al.

    Exploiting the Annexin A1 pathway for the development of novel anti-inflammatory therapeutics

    Br. J. Pharmacol.

    (2009)
  • P. Maderna et al.

    FPR2/ALX receptor expression and internalization are critical for lipoxin A4 and annexin-derived peptide-stimulated phagocytosis

    FASEB J.

    (2010)
  • A.P. Girol et al.

    Anti-inflammatory mechanisms of the annexin A1 protein and its mimetic peptide Ac2-26 in models of ocular inflammation in vivo and in vitro

    J. Immunol.

    (2013)
  • M. Perretti et al.

    Annexin A1 and glucocorticoids as effectors of the resolution of inflammation

    Nat. Rev. Immunol.

    (2009)
  • F.N. Gavins et al.

    Annexin A1 and the regulation of innate and adaptive immunity

    Front. Immunol.

    (2012)
  • L. Parente et al.

    Annexin 1: more than an anti-phospholipase protein

    Inflamm. Res.

    (2004)
  • M.A. Sugimoto et al.

    Annexin A1 and the resolution of inflammation: modulation of neutrophil recruitment, apoptosis, and clearance

    J. Immunol. Res.

    (2016)
  • L.H. Lim et al.

    Annexin 1: the new face of an old molecule

    FASEB J.

    (2007)
  • E. Solito et al.

    A novel calcium-dependent proapoptotic effect of annexin 1 on human neutrophils

    FASEB J.

    (2003)
  • S. McArthur et al.

    Definition of a novel pathway centered on lysophosphatidic acid to recruit monocytes during the resolution phase of tissue inflammation

    J. Immunol.

    (2015)
  • M. Scannell et al.

    Annexin-1 and peptide derivatives are released by apoptotic cells and stimulate phagocytosis of apoptotic neutrophils by macrophages

    J. Immunol.

    (2007)
  • K.E. Blume et al.

    Cell surface externalization of annexin A1 as a failsafe mechanism preventing inflammatory responses during secondary necrosis

    J. Immunol.

    (2009)
  • D. Pupjalis et al.

    Annexin A1 released from apoptotic cells acts through formyl peptide receptors to dampen inflammatory monocyte activation via JAK/STAT/SOCS signalling

    EMBO Mol. Med.

    (2011)
  • Y.H. Yang et al.

    Modulation of inflammation and response to dexamethasone by Annexin 1 in antigen-induced arthritis

    Arthritis Rheum.

    (2004)
  • S.L. Williams et al.

    A proinflammatory role for proteolytically cleaved annexin A1 in neutrophil transendothelial migration

    J. Immunol.

    (2010)
  • R.D. Ye et al.

    International union of basic and clinical pharmacology. LXXIII. Nomenclature for the formyl peptide receptor (FPR) family

    Pharmacol. Rev.

    (2009)
  • Y.H. Yang et al.

    Annexin A1: potential for glucocorticoid sparing in RA

    Nat. Rev. Rheumatol.

    (2013)
  • F.S. Ng et al.

    Annexin-1-deficient mice exhibit spontaneous airway hyperresponsiveness and exacerbated allergen-specific antibody responses in a mouse model of asthma

    Clin. Exp. Allergy

    (2011)
  • Y.H. Yang et al.

    Deficiency of annexin A1 in CD4+ T cells exacerbates T cell-dependent inflammation

    J. Immunol.

    (2013)
  • N. Paschalidis et al.

    Modulation of experimental autoimmune encephalomyelitis by endogenous annexin A1

    J. Neuroinflammation

    (2009)
  • F. D’Acquisto et al.

    Impaired T cell activation and increased Th2 lineage commitment in Annexin-1-deficient T cells

    Eur. J. Immunol.

    (2007)
  • F. D’Acquisto et al.

    Glucocorticoid treatment inhibits annexin-1 expression in rheumatoid arthritis CD4+ T cells

    Rheumatology (Oxford).

    (2008)
  • K. Kurosu et al.

    Identification of annexin 1 as a novel autoantigen in acute exacerbation of idiopathic pulmonary fibrosis

    J. Immunol.

    (2008)
  • R. Biaoxue et al.

    Annexin A1 in malignant tumors: current opinions and controversies

    Int. J. Biol. Markers

    (2014)
  • C. Guo et al.

    Potential role of Anxa1 in cancer

    Future Oncol.

    (2013)
  • Z. Boudhraa et al.

    Annexin A1 localization and its relevance to cancer

    Clin. Sci. (Lond.)

    (2016)
  • K. Polyak

    Heterogeneity in breast cancer

    J. Clin. Invest.

    (2011)
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