S100A2 (S100 calcium binding protein A2)

2011-11-01   Christopher J Scarlett , Andrew V Biankin 

Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria St Darlinghurst, NSW 2010, Australia




Atlas Image
The S100A2 gene spans a total region of 4723 bp (NM_005978.3) consisting of three exons. Exon 1 is untranslated, exon 2 codes for the N-terminal 47 amino acids and exon 3 codes for the C-terminal 50 amino acids.


The nucleotide sequence and genomic organization of the S100A2 gene was originally described by Wicki et al. (1997), using a normal and a tumorigenic breast epithelial cell line. The structure of S100A2 was originally deduced by the analysis of cDNA from a positive genomic clone from an EMBL-3 SP6/T7 human female peripheral blood leukocyte genomic library (Clontech, no. HL 1111j). The human S100A2 gene is located next to the S100A4 locus on chromosome 1q21.3 within a cluster of S100 genes (Wolf et al., 2011), and part of the epidermal differentiation complex (Wolf et al., 2011). The S100A2 gene spans a total region of 4723 bp (NM_005978.3) consisting of three exons. The three-exon-structure contains the coding sequence within exons two and three, reflecting the common composition of S100 genes. Exon 1 is untranslated, exon 2 codes for the N-terminal 47 amino acids and exon 3 codes for the C-terminal 50 amino acids.
The S100A2 gene has a total length of 4723 bp and seven splice variants, which can be categorized into five variants with protein product and two transcripts without an open-reading frame. Four of the variants contain the three-exon structure with the coding sequences in exon 2 and exon 3, while also sharing identical protein sequences only differing in their untranslated 5 region (Wolf et al., 2011).


The S100A2 mRNA product length, including the poly-adenylate stretch, is 970 bp (NM_005978.3). The S100A2 gene has an open-reading frame of 294 nucleotides encoding for a protein of 97 amino acid residues with a molecular mass of 11,117 kDa (NM_005969.1; see below).
Wicki et al. (1997) identified an enhancer element in the promoter region necessary for the transcription of the S100A2 gene. This enhancer element is active in both orientations and either upstream or downstream of the reporter gene, and is both necessary and sufficient for transcription of the gene (Wicki et al., 1997).



The S100A2 gene encodes for a protein of 97 amino acid residues, with a molecular mass of 11,117 kDa (P29034; UniProtKB).
Atlas Image
The protein structure and amino acid sequence of S100A2 (human). Modified from Wolf et al., Amino Acids, 2011.


S100A2 is a member of the S100 family of calcium-binding proteins. The S100A2 gene encodes for a protein of 98 amino acid residues, with a molecular mass of 11,117 kDa (P29034; UniProtKB). S100 proteins are a family of low-molecular weight (9-12 kD), calcium-binding proteins that initiate a number of cellular processes such as cell division, motility, secretion, protein synthesis, and membrane permeability through both calcium dependent and independent mechanism. Greater than twenty five different S100 proteins have so far been identified with many mapping closely together on chromosome 1q21.
S100A2 calcium-binding protein is characterized by four helices, two distinct calcium-binding EF-hand motifs, a central hinge region and C- and N-terminal variable domains. S100 proteins are found in the cytoplasm as preassembled dimers. A potential role for S100 proteins in cancer originated from observations that the evolutionarily conserved gene cluster containing S100 genes on human chromosome 1q21 underwent several rearrangements during tumour development.


S100A2 appears to be tissue specific as it is expressed in many normal and tumour tissues. Expression of S100A2 occurs in normal breast, lung, kidney, prostate, skin and oral squamous cell tissue, with loss of expression observed in associated carcinomas suggesting a putative tumour suppressor role; while in some malignant tissues, such as pancreatic, esophageal, gastric, papillary and follicular thyroid, some subsets of lung cancer and non-small cell lung cancer high expression of S100A2 is associated with poor prognosis and increased metastases. Clearly, expression of S100A2 is not ubiquitous for all tissues and there is evidently an element of tissue-specific expression.


S100A2 is primarily localised in the nucleus with translocation to the cytoplasm evident in a number of tissue types.


Little is known about S100A2 function and its potential contribution as either a tumour suppressor or contributor to tumorigenesis and metastases. Upon calcium binding a conformational change occurs exposing a target protein recognition site. Once in the calcium-activated state each monomer can interact with one target protein. In this state the S100 proteins act as calcium sensors and play a role in protein phosphorylation, enzyme activation via phosphorylation, inflammation, cellular contraction and relaxation by regulating cytoskeletal constituents including actin and myosin, and nuclear transcription promoting cell proliferation and differentiation.


Close relation to S100A4 has been confirmed by sequence analysis. Both proteins share over 60% amino acid sequence identity (Glenney et al., 1989).



Mutations have not been reported.

Implicated in

Entity name
Pancreatic cancer
For pancreatic cancer high S100A2 expression co-segregated with a poor response to pancreatectomy. Patients with tumours that demonstrated high S100A2 expression did not have a significant survival benefit from pancreatectomy compared to biopsy alone, whereas S100A2 negative tumours did. In the subgroup of patients who had resections with clear surgical margins, those whose tumours demonstrated high, or mod/high expression of S100A2 co-segregated with a poor outcome suggesting that occult distant metastatic disease may have been present in patients with tumours that had high S100A2 expression at the time of pancreatectomy. In a supportive study, invasive pancreatic ductal carcinoma cells were shown to express higher levels of S100A2 than did intraductal papillary mucinous neoplasms (IPMN), pancreatitis affected epithelia or normal cells, while cell lines derived from metastatic sites expressed higher levels of S100A2 than those from primary sites. This study also demonstrated that patients with high S100A2 expression had poorer overall survival. Together, these data demonstrate that S100A2 expression is a good predictor of response to pancreatectomy for pancreatic cancer and suggests that high S100A2 expression may be a marker of a metastatic phenotype (Ohuchida et al., 2007; Biankin et al., 2009; Pinese et al., 2009).
Entity name
Esophageal squamous cell carcinoma (ESCC)
S100A2 was initially reported to be downregulated in a cohort of ESCC patients as measured by RT-PCR, with node-negative ESCC patients without S100A2 expression considered to be a high-risk group with poor survival. More recently, however, S100A2-overexpressing cancers showed a trend toward preferentially developing lymph node metastases and distant metastases, suggesting that S100A2 might be related to the progression of esophageal SCC (Kyriazanos et al., 2002; Ji et al., 2004; Imazawa et al., 2005; Cao et al., 2009).
Entity name
Barretts adenocarcinomas
Expression of S100A2 mRNA and protein in Barretts adenocarcinoma samples were performed by RT-PCR, and immunohistochemistry respectively. Frequent overexpression of S100A2 mRNA was observed in Barretts adenocarcinomas, while overexpression of S100A2 protein was more frequently seen in well-differentiated tumours than in others. Contrary to the nuclear expression of S100A2 in normal esophageal mucosa, two thirds of Barretts dysplasia and Barretts adenocarcinomas that overexpressed S100A2 demonstrated stronger cytosolic staining than nuclear staining (Lee et al., 2006).
Entity name
Non-small cell lung cancer (NSCLC)
Many studies have been performed invetigating S100A2 expression in non-small cell lung cancer (NSCLC). Increased expression of S100A2 has been demonstrated in tumour cells, with S100A2 providing valuable prognostic parameters. Patients whose tumours had positive S100A2 expression had a significantly lower overall survival and disease-specific survival rate at 5 years after surgery than did patients with negative S100A2 expression. S100A2 was overexpressed in tumours that metastasized during the course of the disease. Overexpression of S100A2 in NSCLC cell cultures has been shown to increase transendothelial migration, corroborating the role of S100A2 in the metastatic process. High expression of S100A2 is associated with metastasis and predicts survival in early stages of NSCLC. These findings are supported by studies in a mouse model of non-small cell lung cancer (NSCLC) where NOD/SCID mice xenografted with NSCLC cells overexpressing S100A2 demonstrated significantly more metastases than vector alone transfected cells (Heighway et al., 2002; Diederichs et al., 2004; Smith et al., 2004; Wang et al., 2005; Zech et al., 2006; Bartling et al., 2007; Bulk et al., 2009; Strazisar et al., 2009a; Strazisar et al., 2009b).
Entity name
Gastric cancer
Early assessment of S100A2 expression in gastric cancer using serial analysis of gene expression (SAGE) revealed that over 90% of gastric tumours overexpressed S100A2 when compared to normal gastric mucosa. More recently, however, S100A2 protein expression in normal and benign gastric tissues has been reported with a loss of S100A2 expression in 52% of gastric adenocarcinomas. Loss of S100A2 expression was associated with histological differentiation, depth of invasion, lymphatic vessel invasion and lymph node metastasis. These conflicting data demonstrate the need for further studies into S100A2 expression and gastric adenocarcinomas to further elucidate the tumorigenic mechanisms underpinning gastric carcinogenesis (El-Rifai et al., 2002; Liu et al., 2008; Luo et al., 2011).
Entity name
Thyroid carcinomas
For thyroid carcinomas, S100A2 has been demonstrated to contribute to carcinogenic events in papillary carcinoma progression (90% positive), with S100A2 expression being one of the biological characteristics of anaplastic carcinoma (Ito et al., 2005).
Entity name
Ovarian carcinomas (various subtypes) / ovarian serous papillary tumours
S100A2 is highly overexpressed in the majority of ovarian carcinomas irrespective of the subtype, in particular S100A2 is overexpressed in ovarian serous papillary carcinomas compared to normal ovarian cell lines (Hough et al., 2001; Santin et al., 2004).
Entity name
Breast cancer
S100A2 expression in normal mammary epithelium is usually high, with loss of S100A2 associated with the development of malignant breast carcinoma. Studies have revealed that loss of S100A2 expression is not associated with early carcinogenesis from normal mammary epithelium to benign hyperplasia. These experiments provided early evidence that S100A2 repression in tumour cells may be mediated by site-specific methylation. Interestingly, recent investigations have demonstrated that the highly invasive basal breast cancers express significantly higher levels of S100A2 than non-basal breast malignancies (Wicki et al., 1997; Liu et al., 2000; McKiernan et al., 2011).
Entity name
Oral squamous cell carcinoma (OSCC) / laryngeal squamous cell carcinoma (LSCC)
Recent data has emerged surrounding the potential antitumour role of S100A2 in squamous cell carcinomas, partly via reduced expression of COX-2. For oral squamous cell carcinomas (OSCC) a higher rate of late cervical metastasis has been shown in patients with S100A2-negative tumours than those with S100A2-positive tumours, indicating that patients with stage I or II invasive OSCC without S100A2 expression should be considered a high-risk group for late cervical metastasis (poor overall survival). Loss of nuclear S100A2 may also serve as an independent prognostic marker for early-stage oral cancer patients at high risk of recurrence. A more aggressive treatment modality and intensive follow-up may be recommended for the patients with reduced expression of S100A2 in tumour cell nuclei. In laryngeal squamous cell carcinoma, a correlation was found between S100A2 tumour positivity and longer relapse-free and overall survival (Lauriola et al., 2000; Suzuki et al., 2005; Tsai et al., 2005; Tsai et al., 2006; Almadori et al., 2009).
Entity name
Bladder cancer
Conflicting data has emerged concerning S100A2 expression in bladder cancers. Overexpression of S100A2 mRNA has been demonstrated in bladder cancers using RT-PCR, however a study investigating S100A2 expression at the protein level demonstrated that S100A2 expression was significantly decreased in the bladder cancer specimens compared with the controls. The loss of expression of S100A2 and increased expression of another calcium binding protein, S100A4, were associated with muscle invasion with alterations in expression also associated with a greater risk of disease progression and a decreased chance of cancer-specific survival (Matsumoto et al., 2007; Yao et al., 2007).
Entity name
Squamous cell carcinoma of the head and neck (SCCHN)
In oral cancer cells the Ca2+ and cell cycle-dependent p53-S100A2 interaction might modulate proliferation, while for squamous cell carcinomas of the head and neck (SCCHN) it has been postulated that S100A2 may play a role in the metastasis of SCCHN, however most tumours expressed S100A2 but lymph node metastases showed a pattern of reduced staining for S100A2 compared with primary tumours (Mueller et al., 2005; Zhang et al., 2007).
Entity name
Lung adenocarcinoma / lung squamous cell carcinoma (LSCC)
Expression of S100A2 is reportedly downregulated in some lung squamous cell carcinomas, with S100A2 positivity being a favourable prognostic indicator in patients with p53-negative tumours (Feng et al., 2001; Shen et al., 2002; Matsubara et al., 2005).
Entity name
Prostate cancer
S100A2 expression was observed in the basal cells of non-malignant epithelium, while absent S100A2 expression was demonstrated in a cohort of 41 prostate cancer specimens, potentially due to promoter hypermethylation. In benign conditions such as benign prostate hyperplasia and prostatitis, high levels of S100A2 are observed with a progressive loss of S100A2 expression occurring with increasing tumour grade and metastases indicating that loss of S100A2 may be an important event during progression of prostate cancer. More recently, high S100A2 protein expression was observed in a cohort of benign prostatic hyperplasia, with little or no expression in prostate cancer cells, while a concomitant increase of S100A4 expression was observed in prostate cancer cells. These data suggest that the analysis of both S100A2 and S100A4 expression in prostatic tissues may be a useful prognostic indicator for prostate cancer (Gupta et al., 2003; Rehman et al., 2005; Kwon et al., 2010).
Entity name
Malignant melanoma
For malignant melanoma, loss of S100A2 gene expression may be an early event in the development of melanoma. All nevi showed moderate to high expression levels of S100A2, while the expression levels were low in cell lines established from primary melanomas and metastases did not express S100A2 mRNA (Maelandsmo et al., 1997).


Pubmed IDLast YearTitleAuthors
193446082009Diminished expression of S100A2, a putative tumour suppressor, is an independent predictive factor of neck node relapse in laryngeal squamous cell carcinoma.Almadori G et al
176890672007S100A2-S100P expression profile and diagnosis of non-small cell lung carcinoma: impairment by advanced tumour stages and neoadjuvant chemotherapy.Bartling B et al
193761212009Expression of S100A2 calcium-binding protein predicts response to pancreatectomy for pancreatic cancer.Biankin AV et al
191180292009S100A2 induces metastasis in non-small cell lung cancer.Bulk E et al
197251542009Expression and clinical significance of S100A2 and p63 in esophageal carcinoma.Cao LY et al
153138922004S100 family members and trypsinogens are predictors of distant metastasis and survival in early-stage non-small cell lung cancer.Diederichs S et al
124608932002Gastric cancers overexpress S100A calcium-binding proteins.El-Rifai W et al
116918252001Diminished expression of S100A2, a putative tumor suppressor, at early stage of human lung carcinogenesis.Feng G et al
25218611989Isolation of a new member of the S100 protein family: amino acid sequence, tissue, and subcellular distribution.Glenney JR Jr et al
125061782003Differential expression of S100A2 and S100A4 during progression of human prostate adenocarcinoma.Gupta S et al
124000182002Expression profiling of primary non-small cell lung cancer for target identification.Heighway J et al
113587982001Coordinately up-regulated genes in ovarian cancer.Hough CD et al
158650732005S100A2 overexpression is frequently observed in esophageal squamous cell carcinoma.Imazawa M et al
158426392005Expression of S100A2 and S100A6 in thyroid carcinomas.Ito Y et al
151851462004Differential expression of S100 gene family in human esophageal squamous cell carcinoma.Ji J et al
206647772010Significance of S100A2 and S100A4 Expression in the Progression of Prostate Adenocarcinoma.Kwon YW et al
119566172002Expression and prognostic significance of S100A2 protein in squamous cell carcinoma of the esophagus.Kyriazanos ID et al
109564082000Prognostic significance of the Ca(2+) binding protein S100A2 in laryngeal squamous-cell carcinoma.Lauriola L et al
170325012006Expression of calcium-binding proteins S100A2 and S100A4 in Barrett's adenocarcinomas.Lee OJ et al
110766562000Expression of calcium-binding protein S100A2 in breast lesions.Liu D et al
187934472008In silico analysis and verification of S100 gene expression in gastric cancer.Liu J et al
209494682011Loss of Reprimo and S100A2 expression in human gastric adenocarcinoma.Luo J et al
92914411997Differential expression patterns of S100A2, S100A4 and S100A6 during progression of human malignant melanoma.Maelandsmo GM et al
163679032005Differential expression of S100A2 and S100A4 in lung adenocarcinomas: clinicopathological significance, relationship to p53 and identification of their target genes.Matsubara D et al
176889172007Expression of S100A2 and S100A4 predicts for disease progression and patient survival in bladder cancer.Matsumoto K et al
211537242011The role of S100 genes in breast cancer progression.McKiernan E et al
159417202005The calcium-binding protein S100A2 interacts with p53 and modulates its transcriptional activity.Mueller A et al
179409952007Over-expression of S100A2 in pancreatic cancer correlates with progression and poor prognosis.Ohuchida K et al
193991852009Messina: a novel analysis tool to identify biologically relevant molecules in disease.Pinese M et al
160156092005Promoter hyper-methylation of calcium binding proteins S100A6 and S100A2 in human prostate cancer.Rehman I et al
153053712004Gene expression profiles in primary ovarian serous papillary tumors and normal ovarian epithelium: identification of candidate molecular markers for ovarian cancer diagnosis and therapy.Santin AD et al
124457442002Molecular cloning, identification and analysis of lung squamous cell carcinoma-related genes.Shen C et al
154677672004S100A2 is strongly expressed in airway basal cells, preneoplastic bronchial lesions and primary non-small cell lung carcinomas.Smith SL et al
186562792009Frequent polymorphic variations but rare tumour specific mutations of the S100A2 on 1q21 in non-small cell lung cancer.Strazisar M et al
162732442005S100A2 expression as a predictive marker for late cervical metastasis in stage I and II invasive squamous cell carcinoma of the oral cavity.Suzuki F et al
157926062005S100A2, a potential marker for early recurrence in early-stage oral cancer.Tsai ST et al
169085932006Cyclooxygenase-2 is involved in S100A2-mediated tumor suppression in squamous cell carcinoma.Tsai WC et al
158009162005Overexpression of S100A2 protein as a prognostic marker for patients with stage I non small cell lung cancer.Wang H et al
94814751997Repression of the candidate tumor suppressor gene S100A2 in breast cancer is mediated by site-specific hypermethylation.Wicki R et al
205210722011S100A2 in cancerogenesis: a friend or a foe?Wolf S et al
179700442007Expression of S100 protein family members in the pathogenesis of bladder tumors.Yao R et al
170677482006Prognostic and diagnostic relevance of hnRNP A2/B1, hnRNP B1 and S100 A2 in non-small cell lung cancer.Zech VF et al
171233072007Down-regulation of S100A2 in lymph node metastases of head and neck cancer.Zhang X et al

Other Information

Locus ID:

NCBI: 6273
MIM: 176993
HGNC: 10492
Ensembl: ENSG00000196754


dbSNP: 6273
ClinVar: 6273
TCGA: ENSG00000196754


Gene IDTranscript IDUniprot

Expression (GTEx)


Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
192973172009Modulation of the oligomerization state of p53 by differential binding of proteins of the S100 family to p53 monomers and tetramers.47
159417202005The calcium-binding protein S100A2 interacts with p53 and modulates its transcriptional activity.41
191180292009S100A2 induces metastasis in non-small cell lung cancer.28
193761212009Expression of S100A2 calcium-binding protein predicts response to pancreatectomy for pancreatic cancer.22
178741822008The prognostic value of Stathmin-1, S100A2, and SYK proteins in ER-positive primary breast cancer patients treated with adjuvant tamoxifen monotherapy: an immunohistochemical study.21
170325012006Expression of calcium-binding proteins S100A2 and S100A4 in Barrett's adenocarcinomas.17
205914292010S100 proteins interact with the N-terminal domain of MDM2.17
163679032005Differential expression of S100A2 and S100A4 in lung adenocarcinomas: clinicopathological significance, relationship to p53 and identification of their target genes.16
183881312008Transcriptional activation of the tumor suppressor and differentiation gene S100A2 by a novel p63-binding site.16
206770142010An approach based on a genome-wide association study reveals candidate loci for narcolepsy.16


Christopher J Scarlett ; Andrew V Biankin

S100A2 (S100 calcium binding protein A2)

Atlas Genet Cytogenet Oncol Haematol. 2011-11-01

Online version: http://atlasgeneticsoncology.org/gene/42191/s100a2