Invited Review-pharmacology across disciplinesAnnexin A1 influences in breast cancer: Controversies on contributions to tumour, host and immunoediting processes
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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)
- et al.
Annexins: the problem of assessing the biological role for a gene family of multifunctional calcium- and phospholipid-binding proteins
Biochim. Biophys. Acta
(1994) - et al.
Membrane-induced folding and structure of membrane-bound annexin A1 N-terminal peptides: implications for annexin-induced membrane aggregation
Biophys. J .
(2008) - et al.
X-ray structure of full-length annexin 1 and implications for membrane aggregation
J. Mol. Biol.
(2001) - et al.
The complex understanding of Annexin A1 phosphorylation
Cell. Signal.
(2014) - et al.
Selective Secretion of Annexin-1, a Protein without a Signal Sequence, by the Human Prostate-Gland
J. Biol. Chem.
(1991) - et al.
A novel ligand of the formyl peptide receptor
Mol. Cell
(2000) - et al.
Involvement of the receptor for formylated peptides in the in vivo anti-migratory actions of annexin 1 and its mimetics
Am. J. Pathol.
(2001) - et al.
Design and characterization of a cleavage-resistant Annexin A1 mutant to control inflammation in the microvasculature
Blood
(2010) - et al.
Annexin 1 and its bioactive peptide inhibit neutrophil-endothelium interactions under flow: indication of distinct receptor involvement
Blood
(2006) - et al.
Functional and ultrastructural analysis of annexin A1 and its receptor in extravasating neutrophils during acute inflammation
Am. J. Pathol.
(2009)
Detection of intracellular lipocortin 1 in human leukocyte subsets
Clin. Immunol. Immunopathol.
Comparative analysis of Annexin A1-formyl peptide receptor 2/ALX expression in human leukocyte subsets
Int. Immunopharmacol.
On the adaptive nature of annexin-A1
Curr. Opin. Pharmacol.
Characterization of basal-like breast cancer: an update
Diagn. Histopathol.
Decreased expression of annexin A1 is correlated with breast cancer development and progression as determined by a tissue microarray analysis
Hum. Pathol.
Annexin-A1 controls an ERK-RhoA-NFkappaB activation loop in breast cancer cells
Biochem. Biophys. Res. Commun.
The role of annexin A1 in expression of matrix metalloproteinase-9 and invasion of breast cancer cells
Biochem. Biophys. Res. Commun.
Hallmarks of cancer: the next generation
Cell
Somatic cell fusions reveal extensive heterogeneity in basal-like Breast cancer
Cell Rep.
New insights into cancer immunoediting and its three component phases-elimination, equilibrium and escape
Curr. Opin. Immunol.
Macrophage polarization in tumour progression
Semin. Cancer Biol.
Annexins: from structure to function
Physiol. Rev.
Annexins: linking Ca2+ signalling to membrane dynamics
Nat. Rev. Mol. Cell Biol.
Exploiting the Annexin A1 pathway for the development of novel anti-inflammatory therapeutics
Br. J. Pharmacol.
FPR2/ALX receptor expression and internalization are critical for lipoxin A4 and annexin-derived peptide-stimulated phagocytosis
FASEB J.
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.
Annexin A1 and glucocorticoids as effectors of the resolution of inflammation
Nat. Rev. Immunol.
Annexin A1 and the regulation of innate and adaptive immunity
Front. Immunol.
Annexin 1: more than an anti-phospholipase protein
Inflamm. Res.
Annexin A1 and the resolution of inflammation: modulation of neutrophil recruitment, apoptosis, and clearance
J. Immunol. Res.
Annexin 1: the new face of an old molecule
FASEB J.
A novel calcium-dependent proapoptotic effect of annexin 1 on human neutrophils
FASEB J.
Definition of a novel pathway centered on lysophosphatidic acid to recruit monocytes during the resolution phase of tissue inflammation
J. Immunol.
Annexin-1 and peptide derivatives are released by apoptotic cells and stimulate phagocytosis of apoptotic neutrophils by macrophages
J. Immunol.
Cell surface externalization of annexin A1 as a failsafe mechanism preventing inflammatory responses during secondary necrosis
J. Immunol.
Annexin A1 released from apoptotic cells acts through formyl peptide receptors to dampen inflammatory monocyte activation via JAK/STAT/SOCS signalling
EMBO Mol. Med.
Modulation of inflammation and response to dexamethasone by Annexin 1 in antigen-induced arthritis
Arthritis Rheum.
A proinflammatory role for proteolytically cleaved annexin A1 in neutrophil transendothelial migration
J. Immunol.
International union of basic and clinical pharmacology. LXXIII. Nomenclature for the formyl peptide receptor (FPR) family
Pharmacol. Rev.
Annexin A1: potential for glucocorticoid sparing in RA
Nat. Rev. Rheumatol.
Annexin-1-deficient mice exhibit spontaneous airway hyperresponsiveness and exacerbated allergen-specific antibody responses in a mouse model of asthma
Clin. Exp. Allergy
Deficiency of annexin A1 in CD4+ T cells exacerbates T cell-dependent inflammation
J. Immunol.
Modulation of experimental autoimmune encephalomyelitis by endogenous annexin A1
J. Neuroinflammation
Impaired T cell activation and increased Th2 lineage commitment in Annexin-1-deficient T cells
Eur. J. Immunol.
Glucocorticoid treatment inhibits annexin-1 expression in rheumatoid arthritis CD4+ T cells
Rheumatology (Oxford).
Identification of annexin 1 as a novel autoantigen in acute exacerbation of idiopathic pulmonary fibrosis
J. Immunol.
Annexin A1 in malignant tumors: current opinions and controversies
Int. J. Biol. Markers
Potential role of Anxa1 in cancer
Future Oncol.
Annexin A1 localization and its relevance to cancer
Clin. Sci. (Lond.)
Heterogeneity in breast cancer
J. Clin. Invest.
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2019, Trends in Molecular MedicineCitation Excerpt :The difference in the biological functions between the members of the superfamily is attributed to the difference in N-terminal domain, as it is the site where most post-translational modifications occur [2]. In the absence of calcium, the N terminus is hidden within the core C terminus, while the presence of calcium results in a conformational change to expose the N terminus [3]. ANXA1 was discovered to mediate the anti-inflammatory effect of glucocorticoids, where it inhibits the action of phospholipase A2, limiting the supply of arachidonic acids needed for the synthesis of prostaglandins, thus suppressing inflammation.
Assessment of annexin A1 release during immunogenic cell death
2019, Methods in EnzymologyCitation Excerpt :Conversely, ANXA1 expression is downregulated in esophageal carcinoma (Moghanibashi et al., 2012; Xia et al., 2002), laryngeal cancer (Silistino-Souza et al., 2007) nasopharyngeal cancer (Cheng et al., 2008), oral squamous cell carcinoma (Koike et al., 2005; Zhang et al., 2009), prostate cancer (Kang et al., 2002; Patton, Chen, Joseph, & Yang, 2005; Paweletz et al., 2000) and lymphoma (Vishwanatha, Salazar, & Gopalakrishnan, 2004). In other tumors, such as bladder, gastric and breast cancer or leukemia, the levels of ANXA1 expression are variable (Guo, Liu, & Sun, 2013; Tu, Johnstone, & Stewart, 2017). Vacchelli et al. recently showed that ANXA1 has a critical role in establishing a specific anti-tumor immune response following immunogenic chemotherapy.