Gene Summary

Gene:CA12; carbonic anhydrase XII
Aliases: CAXII, HsT18816
Summary:Carbonic anhydrases (CAs) are a large family of zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide. They participate in a variety of biological processes, including respiration, calcification, acid-base balance, bone resorption, and the formation of aqueous humor, cerebrospinal fluid, saliva, and gastric acid. This gene product is a type I membrane protein that is highly expressed in normal tissues, such as kidney, colon and pancreas, and has been found to be overexpressed in 10% of clear cell renal carcinomas. Three transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Jun 2014]
Databases:OMIM, HGNC, GeneCard, Gene
Protein:carbonic anhydrase 12
Source:NCBIAccessed: 21 August, 2015


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 21 August 2015 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 21 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: CA12 (cancer-related)

Zheng B, Liu J, Gu J, et al.
A three-gene panel that distinguishes benign from malignant thyroid nodules.
Int J Cancer. 2015; 136(7):1646-54 [PubMed] Related Publications
Reliable preoperative diagnosis of malignant thyroid tumors remains challenging because of the inconclusive cytological examination of fine-needle aspiration biopsies. Although numerous studies have successfully demonstrated the use of high-throughput molecular diagnostics in cancer prediction, the application of microarrays in routine clinical use remains limited. Our aim was, therefore, to identify a small subset of genes to develop a practical and inexpensive diagnostic tool for clinical use. We developed a two-step feature selection method composed of a linear models for microarray data (LIMMA) linear model and an iterative Bayesian model averaging model to identify a suitable gene set signature. Using one public dataset for training, we discovered a three-gene signature dipeptidyl-peptidase 4 (DPP4), secretogranin V (SCG5) and carbonic anhydrase XII (CA12). We then evaluated the robustness of our gene set using three other independent public datasets. The gene signature accuracy was 85.7, 78.8 and 85.7%, respectively. For experimental validation, we collected 70 thyroid samples from surgery and our three-gene signature method achieved an accuracy of 94.3% by quantitative polymerase chain reaction (QPCR) experiment. Furthermore, immunohistochemistry in 29 samples showed proteins expressed by these three genes are also differentially expressed in thyroid samples. Our protocol discovered a robust three-gene signature that can distinguish benign from malignant thyroid tumors, which will have daily clinical application.

Kim HJ, Chung JH, Shin HP, et al.
Polymorphisms of interferon gamma gene and risk of hepatocellular carcinoma in Korean patients with chronic hepatitis B viral infection.
Hepatogastroenterology. 2013 Nov-Dec; 60(128):2080-4 [PubMed] Related Publications
BACKGROUNDS/AIMS: Increasing evidence supports the contribution of the pro-/anti-inflammatory cytokine balance and genetic factors to hepatocellular carcinoma (HCC). Here, we investigated whether genetic interferon gamma polymorphisms were associated with HCC in Korean patients with chronic hepatitis B.
METHODOLOGY: We genotyped a single nucleotide polymorphism (SNP, rs2430561, +874A/T) and a microsatellite (rs3138557, (CA) (n) repeat), located in the first intron of the interferon gamma gene, by direct sequencing and the gene scan method. A population-based case-control study of HCC was conducted and included 170 patients with chronic hepatitis and HCC, and 171 with chronic hepatitis B patients without hepatocellular carcinoma in a Korean population.
RESULTS: Genotype and allele distributions of the interferon gamma gene SNP were associated with HCC. The frequencies of the AA genotype and the A allele were significantly increased in hepatocellular carcinoma subjects (p < 0.05). Combined analysis using the genotype of rs2430561 and the number of microsatellites revealed that the frequencies of AT-CA12, and TT-CA12 increased significantly in hepatocellular carcinoma subjects (p < 0.0001).
CONCLUSIONS: Our results suggest that the interferon gamma gene may be a susceptibility gene and a risk factor for HCC in the Korean population.

Buchholtz ML, Brüning A, Mylonas I, Jückstock J
Epigenetic silencing of the LDOC1 tumor suppressor gene in ovarian cancer cells.
Arch Gynecol Obstet. 2014; 290(1):149-54 [PubMed] Related Publications
PURPOSE: Due to very unspecific symptoms ovarian cancer often is diagnosed only at a late stage of the disease. Thus, morbidity and mortality of the patients are high. Even the established tumor marker CA12-5 shows only low specificity, rising the need for alternative biomarkers capable of detecting early stages of ovarian cancer. We analyzed the expression of the tumor suppressor candidate gene LDOC1 (leucine zipper downregulated in cancer 1) as a potential early biomarker in ovarian cancer cell lines.
METHODS: A total of seven ovarian cancer cell lines were analyzed by RT-PCR (reverse transcriptase polymerase chain reaction) and real-time PCR for expression of LDOC1. Verification of promoter methylation was performed using methylation-specific primers on bisulfite-modified genomic DNA.
RESULTS: Three out of seven ovarian cancer cell lines showed a complete loss of LDOC1 gene expression. LDOC1 silencing was caused neither by gene deletion nor gene rearrangements, but by methylation and subsequent inactivation of the concerned promoter as proofed by methylation specific primers. Similarly, promoter methylation could be inhibited by adding AdC (5-aza-2'-deoxycytidine), an inhibitor of DNA methyltransferases. As a result, a reactivation of the LDOC1 gene was seen.
CONCLUSIONS: The tumor suppressor gene LDOC1 in ovarian cancer cell lines is downregulated by promoter methylation and thus may serve as an early biomarker. Further investigation will show if detection of methylated LDOC1 in peripheral blood has both adequate sensitivity and specificity for a timely non-invasive detection of ovarian cancer.

Takacova M, Bullova P, Simko V, et al.
Expression pattern of carbonic anhydrase IX in Medullary thyroid carcinoma supports a role for RET-mediated activation of the HIF pathway.
Am J Pathol. 2014; 184(4):953-65 [PubMed] Related Publications
Medullary thyroid carcinoma is a relatively rare tumor with poor prognosis and therapy response. Its phenotype is determined by both genetic alterations (activating RET oncoprotein) and physiological stresses, namely hypoxia [activating hypoxia-inducible factor (HIF)]. Here, we investigated the cooperation between these two mechanisms. The idea emerged from the immunohistochemical analysis of carbonic anhydrases (CA) IX and XII expression in thyroid cancer. Although CAXII was present in all types of thyroid carcinomas, CAIX, a direct HIF target implicated in tumor progression, was associated with aggressive medullary and anaplastic carcinomas, and its expression pattern in medullary thyroid carcinomas suggested contribution of both hypoxic and oncogenic signaling. Therefore, we analyzed the CA9 promoter activity in transfected tumor cells expressing RET and/or the HIF-α subunit. We showed that overexpression of both wild-type and mutant RET can increase the CA9 promoter activity induced by HIF-1 (but not HIF-2) in hypoxia. Similar results were obtained with another HIF-1-regulated promoter derived from the lactate dehydrogenase A gene. Moreover, inhibition of the major kinase pathways, which transmit signals from RET and regulate HIF-1, abrogated their cooperative effect on the CA9 promoter. Thus, we brought the first experimental evidence for the crosstalk between RET and HIF-1 that can explain the increased expression of CAIX in medullary thyroid carcinoma and provide a rationale for therapy simultaneously targeting both pathways.

Christgen M, Geffers R, Kreipe H, Lehmann U
IPH-926 lobular breast cancer cells are triple-negative but their microarray profile uncovers a luminal subtype.
Cancer Sci. 2013; 104(12):1726-30 [PubMed] Related Publications
Human primary breast cancers and breast cancer cell lines are classified by microarray-defined molecular subtypes, which reflect differentiation characteristics. Estrogen receptor (ER) expression is indicative of the luminal molecular subtype. We have previously established IPH-926, the first well-characterized cell line from infiltrating lobular breast cancer. IPH-926 displays an ER/PR/ErbB2 triple-negative immunophenotype, which is due to a loss of ER expression in its in vivo clonal ancestry. Loss of ER might indicate a fundamental change of cellular differentiation and it is unclear whether a luminal subtype is preserved beyond ER conversion. Using Affymetrix microarray analysis, seven different classifier gene lists (PAM305, DISC256, TN1288, PAM50, UNC1300, LAB704, INT500) and a background population of 50 common mammary carcinoma cell lines, we have now determined the molecular subtype of IPH-926. Strikingly, the IPH-926 expression profile is highly consistent with a luminal subtype. It is nearest to luminal/ER-positive breast cancer cell lines and far apart from basal breast cancer cell lines. Quantitative real-time RT-PCR confirmed enhanced expression of luminal marker genes (AGR2, CLU, CA12, EMP2, CLDN3) and low or absent expression of basal marker genes (KRT5, CD44, CAV1, VIM). Moreover, IPH-926 lacked androgen receptor (AR) expression, a transcription factor previously associated with luminal-like gene expression in a subset of triple-negative or molecular apocrine breast cancers. In conclusion, IPH-926 is triple-negative but belongs to the luminal subtype. Luminal differentiation characteristics can be preserved beyond ER conversion and might not require a compensatory expression of AR.

Pogue-Geile KL, Kim C, Jeong JH, et al.
Predicting degree of benefit from adjuvant trastuzumab in NSABP trial B-31.
J Natl Cancer Inst. 2013; 105(23):1782-8 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-31 suggested the efficacy of adjuvant trastuzumab, even in HER2-negative breast cancer. This finding prompted us to develop a predictive model for degree of benefit from trastuzumab using archived tumor blocks from B-31.
METHODS: Case subjects with tumor blocks were randomly divided into discovery (n = 588) and confirmation cohorts (n = 991). A predictive model was built from the discovery cohort through gene expression profiling of 462 genes with nCounter assay. A predefined cut point for the predictive model was tested in the confirmation cohort. Gene-by-treatment interaction was tested with Cox models, and correlations between variables were assessed with Spearman correlation. Principal component analysis was performed on the final set of selected genes. All statistical tests were two-sided.
RESULTS: Eight predictive genes associated with HER2 (ERBB2, c17orf37, GRB7) or ER (ESR1, NAT1, GATA3, CA12, IGF1R) were selected for model building. Three-dimensional subset treatment effect pattern plot using two principal components of these genes was used to identify a subset with no benefit from trastuzumab, characterized by intermediate-level ERBB2 and high-level ESR1 mRNA expression. In the confirmation set, the predefined cut points for this model classified patients into three subsets with differential benefit from trastuzumab with hazard ratios of 1.58 (95% confidence interval [CI] = 0.67 to 3.69; P = .29; n = 100), 0.60 (95% CI = 0.41 to 0.89; P = .01; n = 449), and 0.28 (95% CI = 0.20 to 0.41; P < .001; n = 442; P(interaction) between the model and trastuzumab < .001).
CONCLUSIONS: We developed a gene expression-based predictive model for degree of benefit from trastuzumab and demonstrated that HER2-negative tumors belong to the moderate benefit group, thus providing justification for testing trastuzumab in HER2-negative patients (NSABP B-47).

Valet F, de Cremoux P, Spyratos F, et al.
Challenging single- and multi-probesets gene expression signatures of pathological complete response to neoadjuvant chemotherapy in breast cancer: experience of the REMAGUS 02 phase II trial.
Breast. 2013; 22(6):1052-9 [PubMed] Related Publications
This study was designed to identify predictive signatures of pathological complete response (pCR) in breast cancer treated by taxane-based regimen, using clinicopathological variables and transcriptomic data (Affymetrix Hgu133 Plus 2.0 devices). The REMAGUS 02 trial (n = 153,training set) and the publicly available M.D. Anderson data set (n = 133, validation set) were used. A re-sampling method was applied. All predictive models were defined using logistic regression and their classification performances were tested through Area Under the Curve (AUC) estimation. A stable set of 42 probesets (31 genes) differentiate pCR or no pCR samples. Single-or 2-probesets signatures, mainly related to ER pathway, were equally predictive of pCR with AUC greater then 0.80. Models including probesets associated with ESR1, MAPT, CA12 or PIGH presented good classification performances. When clinical variables were entered into the model, only CA12 and PIGH, remained informative (p = 0.05 and p = 0.005) showing that a combination of a few genes provided robust and reliable prediction of pCR.

Kim HJ, Chung JH, Shin HP, et al.
Polymorphisms of interferon gamma gene and risk of hepatocellular carcinoma in korean patients with chronic hepatitis B viral infection.
Hepatogastroenterology. 2013 Jul-Aug; 60(125):1117-20 [PubMed] Related Publications
BACKGROUNDS/AIMS: Increasing evidence supports the contribution of the pro-/anti-inflammatory cytokine balance and genetic factors to hepatocellular carcinoma (HCC). Here, we investigated whether genetic interferon gamma polymorphisms were associated with HCC in Korean patients with chronic hepatitis B.
METHODOLOGY: We genotyped a single nucleotide polymorphism (SNP, rs2430561, +874A/T) and a microsatellite (rs3138557, (CA)n repeat), located in the first intron of the interferon gamma gene, by direct sequencing and the gene scan method. A population-based case-control study of HCC was conducted and included 170 patients with chronic hepatitis and HCC, and 171 with chronic hepatitis B patients without hepatocellular carcinoma in a Korean population.
RESULTS: Genotype and allele distributions of the interferon gamma gene SNP were associated with HCC. The frequencies of the AA genotype and the A allele were significantly increased in hepatocellular carcinoma subjects (p<0.05). Combined analysis using the genotype of rs2430561 and the number of microsatellites revealed that the frequencies of AT-CA12 and TT-CA12 increased significantly in hepatocellular carcinoma subjects (p<0.0001).
CONCLUSIONS: Our results suggest that the interferon gamma gene may be a susceptibility gene and a risk factor for HCC in the Korean population.

Chiche J, Ricci JE, Pouysségur J
Tumor hypoxia and metabolism -- towards novel anticancer approaches.
Ann Endocrinol (Paris). 2013; 74(2):111-4 [PubMed] Related Publications
The transcription factor hypoxia-inducible factor-1 (HIF-1) facilitates the induction of enzymes necessary for regulation of biological processes required for cell survival and the acquisition of an aggressive and invasive phenotype, such as regulation of the intracellular pH (pHi), anaerobic glycolysis, angiogenesis, migration/invasion... In this presentation, we will highlight some of the HIF-1-induced gene products - carbonic anhydrases IX and XII (CAs) and monocarboxylate transporters (MCTs) - which regulate the pHi by controlling export of metabolically-generated acids (carbonic and lactic acids). We reported that targeting these pHi-regulated processes through inhibition of either HIF-1-induced CAIX/CAXII or HIF-1-induced MCT4, MCT1 or Basigin/EMMPRIN/CD147 chaperone of MCTs, severely restricts glycolysis-generated ATP levels and tumor growth. In addition, we demonstrated that the Myc/HIF-1-targeted glyceraldehyde-3-phosphate dehydrogenase (GAPDH) catalyzing a key step producing the NADH cofactor, activates the Akt pathway, thereby upregulating expression of the anti-apoptotic Bcl-xL. As a consequence, high expression of GAPDH contributes to tumor aggressiveness, in particular in the context Myc-driven B lymphomas. We propose that membrane-bound carbonic anhydrases (CAIX, CAXII), monocarboxylate transporters/chaperon Basigin (Myc-induced MCT1 and HIF-induced-MCT4) and GAPDH that are associated with exacerbated tumor metabolism, represent new potential targets for anticancer therapy.

Vermeulen JF, Kornegoor R, van der Wall E, et al.
Differential expression of growth factor receptors and membrane-bound tumor markers for imaging in male and female breast cancer.
PLoS One. 2013; 8(1):e53353 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Male breast cancer accounts for 0.5-1% of all breast cancers and is generally diagnosed at higher stage than female breast cancers and therefore might benefit from earlier detection and targeted therapy. Except for HER2 and EGFR, little is known about expression of growth factor receptors in male breast cancer. We therefore investigated expression profiles of growth factor receptors and membrane-bound tumor markers in male breast cancer and gynecomastia, in comparison with female breast cancer.
METHODS: Tissue microarrays containing 133 male breast cancer and 32 gynecomastia cases were stained by immunohistochemistry for a panel of membrane-bound targets and compared with data on 266 female breast cancers.
RESULTS: Growth factor receptors were variably expressed in 4.5% (MET) up to 38.5% (IGF1-R) of male breast cancers. Compared to female breast cancer, IGF1-R and carbonic anhydrase 12 (CAXII) were more frequently and CD44v6, MET and FGFR2 less frequently expressed in male breast cancer. Expression of EGFR, HER2, CAIX, and GLUT1 was not significantly different between male and female breast cancer. Further, 48.1% of male breast cancers expressed at least one and 18.0% expressed multiple growth factor receptors. Since individual membrane receptors are expressed in only half of male breast cancers, a panel of membrane markers will be required for molecular imaging strategies to reach sensitivity. A potential panel of markers for molecular imaging, consisting of EGFR, IGF1-R, FGFR2, CD44v6, CAXII, GLUT1, and CD44v6 was positive in 77% of male breast cancers, comparable to female breast cancers.
CONCLUSIONS: Expression patterns of growth factor receptors and hypoxia membrane proteins in male breast cancer are different from female breast cancer. For molecular imaging strategies, a putative panel consisting of markers for EGFR, IGF1-R, FGFR2, GLUT1, CAXII, CD44v6 was positive in 77% of cases and might be considered for development of molecular tracers for male breast cancer.

Abend M, Pfeiffer RM, Ruf C, et al.
Iodine-131 dose dependent gene expression in thyroid cancers and corresponding normal tissues following the Chernobyl accident.
PLoS One. 2012; 7(7):e39103 [PubMed] Free Access to Full Article Related Publications
The strong and consistent relationship between irradiation at a young age and subsequent thyroid cancer provides an excellent model for studying radiation carcinogenesis in humans. We thus evaluated differential gene expression in thyroid tissue in relation to iodine-131 (I-131) doses received from the Chernobyl accident. Sixty three of 104 papillary thyroid cancers diagnosed between 1998 and 2008 in the Ukrainian-American cohort with individual I-131 thyroid dose estimates had paired RNA specimens from fresh frozen tumor (T) and normal (N) tissue provided by the Chernobyl Tissue Bank and satisfied quality control criteria. We first hybridized 32 randomly allocated RNA specimen pairs (T/N) on 64 whole genome microarrays (Agilent, 4×44 K). Associations of differential gene expression (log(2)(T/N)) with dose were assessed using Kruskall-Wallis and trend tests in linear mixed regression models. While none of the genes withstood correction for the false discovery rate, we selected 75 genes with a priori evidence or P kruskall/P trend <0.0005 for validation by qRT-PCR on the remaining 31 RNA specimen pairs (T/N). The qRT-PCR data were analyzed using linear mixed regression models that included radiation dose as a categorical or ordinal variable. Eleven of 75 qRT-PCR assayed genes (ACVR2A, AJAP1, CA12, CDK12, FAM38A, GALNT7, LMO3, MTA1, SLC19A1, SLC43A3, ZNF493) were confirmed to have a statistically significant differential dose-expression relationship. Our study is among the first to provide direct human data on long term differential gene expression in relation to individual I-131 doses and to identify a set of genes potentially important in radiation carcinogenesis.

Kowalewska M, Radziszewski J, Goryca K, et al.
Estimation of groin recurrence risk in patients with squamous cell vulvar carcinoma by the assessment of marker gene expression in the lymph nodes.
BMC Cancer. 2012; 12:223 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Regional lymph node (LN) status is a well-known prognostic factor for vulvar carcinoma (VC) patients. Although the reliable LN assessment in VC is crucial, it presents significant diagnostic problems. We aimed to identify specific mRNA markers of VC dissemination in the LN and to address the feasibility of predicting the risk of nodal recurrence by the patterns of gene expression.
METHODS: Sentinel and inguinal LN samples from 20 patients who had undergone surgery for stage T(1-3), N(0-2), M(0) primary vulvar squamous cell carcinoma were analyzed. Gene expression profiles were assessed in four metastatic [LN(+)] and four histologically negative [LN(-)] lymph node samples obtained from four VC patients, by the Affymetrix U133 Plus 2.0 gene expression microarrays. Of the set of genes of the highest expression in the metastatic LNs compared to LN(-), seven candidate marker genes were selected: PERP, S100A8, FABP5, SFN, CA12, JUP and CSTA, and the expression levels of these genes were further analyzed by the real-time reverse transcription polymerase chain reaction (qRT-PCR) in 71 LN samples.
RESULTS: All of the seven genes in question were significantly increased in LN(+) compared to LN(-) samples. In the initial validation of the seven putative markers of metastatic LN, the Cox proportional hazard model pointed to SFN, CA12 and JUP expression to significantly relate to the time to groin recurrence in VC patients.
CONCLUSIONS: Our findings first provided evidence that SFN, CA12 and JUP have a potential of marker genes for the prediction of the groin recurrence LN in VC patients.

McIntyre A, Patiar S, Wigfield S, et al.
Carbonic anhydrase IX promotes tumor growth and necrosis in vivo and inhibition enhances anti-VEGF therapy.
Clin Cancer Res. 2012; 18(11):3100-11 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Bevacizumab, an anti-VEGFA antibody, inhibits the developing vasculature of tumors, but resistance is common. Antiangiogenic therapy induces hypoxia and we observed increased expression of hypoxia-regulated genes, including carbonic anhydrase IX (CAIX), in response to bevacizumab treatment in xenografts. CAIX expression correlates with poor prognosis in most tumor types and with worse outcome in bevacizumab-treated patients with metastatic colorectal cancer, malignant astrocytoma, and recurrent malignant glioma.
EXPERIMENTAL DESIGN: We knocked down CAIX expression by short hairpin RNA in a colon cancer (HT29) and a glioblastoma (U87) cell line which have high hypoxic induction of CAIX and overexpressed CAIX in HCT116 cells which has low CAIX. We investigated the effect on growth rate in three-dimensional (3D) culture and in vivo, and examined the effect of CAIX knockdown in combination with bevacizumab.
RESULTS: CAIX expression was associated with increased growth rate in spheroids and in vivo. Surprisingly, CAIX expression was associated with increased necrosis and apoptosis in vivo and in vitro. We found that acidity inhibits CAIX activity over the pH range found in tumors (pK = 6.84), and this may be the mechanism whereby excess acid self-limits the build-up of extracellular acid. Expression of another hypoxia inducible CA isoform, CAXII, was upregulated in 3D but not two-dimensional culture in response to CAIX knockdown. CAIX knockdown enhanced the effect of bevacizumab treatment, reducing tumor growth rate in vivo.
CONCLUSION: This work provides evidence that inhibition of the hypoxic adaptation to antiangiogenic therapy enhances bevacizumab treatment and highlights the value of developing small molecules or antibodies which inhibit CAIX for combination therapy.

Tafreshi NK, Bui MM, Bishop K, et al.
Noninvasive detection of breast cancer lymph node metastasis using carbonic anhydrases IX and XII targeted imaging probes.
Clin Cancer Res. 2012; 18(1):207-19 [PubMed] Free Access to Full Article Related Publications
PURPOSE: To develop targeted molecular imaging probes for the noninvasive detection of breast cancer lymph node metastasis.
EXPERIMENTAL DESIGN: Six cell surface or secreted markers were identified by expression profiling and from the literature as being highly expressed in breast cancer lymph node metastases. Two of these markers were cell surface carbonic anhydrase isozymes (CAIX and/or CAXII) and were validated for protein expression by immunohistochemistry of patient tissue samples on a breast cancer tissue microarray containing 47 normal breast tissue samples, 42 ductal carcinoma in situ, 43 invasive ductal carcinomas without metastasis, 46 invasive ductal carcinomas with metastasis, and 49 lymph node macrometastases of breast carcinoma. Targeted probes were developed by conjugation of CAIX- and CAXII-specific monoclonal antibodies to a near-infrared fluorescent dye.
RESULTS: Together, these two markers were expressed in 100% of the lymph node metastases surveyed. Selectivity of the imaging probes were confirmed by intravenous injection into nude mice-bearing mammary fat pad tumors of marker-expressing cells and nonexpressing cells or by preinjection of unlabeled antibody. Imaging of lymph node metastases showed that peritumorally injected probes detected nodes harboring metastatic tumor cells. As few as 1,000 cells were detected, as determined by implanting, under ultrasound guidance, a range in number of CAIX- and CAXII-expressing cells into the axillary lymph nodes.
CONCLUSION: These imaging probes have potential for noninvasive staging of breast cancer in the clinic and elimination of unneeded surgery, which is costly and associated with morbidities.

Davidson B, Stavnes HT, Risberg B, et al.
Gene expression signatures differentiate adenocarcinoma of lung and breast origin in effusions.
Hum Pathol. 2012; 43(5):684-94 [PubMed] Related Publications
Lung and breast adenocarcinoma at advanced stages commonly involve the serosal cavities, giving rise to malignant effusions. The aim of the present study was to compare the global gene expression patterns of metastases from these 2 malignancies, to expand and improve the diagnostic panel of biomarkers currently available for their differential diagnosis, as well as to define type-specific biological targets. Gene expression profiles of 7 breast and 4 lung adenocarcinoma effusions were analyzed using the HumanRef-8 BeadChip from Illumina. Differentially expressed candidate genes were validated using quantitative real-time polymerase chain reaction and immunohistochemistry. Unsupervised hierarchical clustering using all 54,675 genes in the array separated lung from breast adenocarcinoma samples. We identified 289 unique probes that were significantly differentially expressed in the 2 cancers by greater than 2-fold using moderated t statistics, of which 65 and 224 were overexpressed in breast and lung adenocarcinoma, respectively. Genes overexpressed in breast adenocarcinoma included TFF1, TFF3, FOXA1, CA12, PITX1, RARRES1, CITED4, MYC, TFAP2A, EFHD1, TOB1, SPDEF, FASN, and TH. Genes overexpressed in lung adenocarcinoma included TITF1, SFTPG, MMP7, EVA1, GPR116, HOP, SCGB3A2, and MET. The differential expression of 15 genes was validated by quantitative real-time PCR, and differences in 8 gene products were confirmed by immunohistochemistry. Expression profiling distinguishes breast adenocarcinoma from lung adenocarcinoma and identifies genes that are differentially expressed in these 2 tumor types. The molecular signatures unique to these cancers may facilitate their differential diagnosis and may provide a molecular basis for therapeutic target discovery.

Yu DH, Li JH, Wang YC, et al.
Serum anti-p53 antibody detection in carcinomas and the predictive values of serum p53 antibodies, carcino-embryonic antigen and carbohydrate antigen 12-5 in the neoadjuvant chemotherapy treatment for III stage non-small cell lung cancer patients.
Clin Chim Acta. 2011; 412(11-12):930-5 [PubMed] Related Publications
BACKGROUND: The serum p53 antibody (s-p53 Ab) is a valuable prognostic factor for carcinomas, but its common detection method, based on enzyme linked immunosorbent assay (ELISA), needs to be improved due to low sensitivity. Although neoadjuvant chemotherapy (NACT) is widely used in the treatment of non-small cell lung cancer (NSCLC) in China, forecasting chemoresistance is still a pressing problem.
METHODS: Hybrid phage and wild-type p53 protein (wt p53 protein) were produced before the establishment of phage-ELISA and p53-ELISA. S-p53 Abs of 829 patients with various types of cancer was detected by a double ELISA system. 47 ΙΙΙ stage NSCLC patients treated with mitomycin, vindesine and cisplatin (MCV)-based NACT were chosen for s-p53 Abs, carcino-embryonic antigen (CEA) and carbohydrate antigen (CA) 12-5 predictive value analysis.
RESULTS: Through the combination of p53-ELISA and phage-ELISA (p53-phage ELISA), the sensitivity of s-p53 Abs in lung, breast, colorectal, gastric, esophageal, liver and ovarian cancer increased to 39.0%, 33.3%, 41.7%, 32.1%, 30.9%, 23.1% and 43.2% respectively. S-p53 Abs proved to correlate with nodal involvement, TNM stage, histological type (in lung cancer) or tumor size (in gastric cancer). As for the 47 ΙΙΙ stage NSCLC treated with NACT, s-p53 Abs and CA12-5 remarkably decreased after NACT treatment (P=0.034 and P=0.007) and pre-NACT low s-p53 Abs correlated with high objective chemoresponse rate (P=0.016).
CONCLUSIONS: p53-phage ELISA system has an edge over single p53-ELISA. S-p53 Abs level correlates with cancer patients' clinicalpathological parameters and can predict the chemoresponse of ΙΙΙ stage NSCLC patients during MCV-based NACT treatment.

Yoo CW, Nam BH, Kim JY, et al.
Carbonic anhydrase XII expression is associated with histologic grade of cervical cancer and superior radiotherapy outcome.
Radiat Oncol. 2010; 5:101 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: To investigate whether expression of carbonic anhydrase XII (CA12) is associated with histologic grade of the tumors and radiotherapy outcomes of the patients with invasive cervical cancer.
METHODS: CA12 expression was examined by immunohistochemical stains in cervical cancer tissues from 183 radiotherapy patients. Histological grading was classified as well (WD), moderately (MD) or poorly differentiated (PD). Oligonucleotide microarray experiment was performed using seven cervical cancer samples to examine differentially expressed genes between WD and PD cervical cancers. The association between CA12 and histological grade was analyzed by chi-square test. CA12 and histological grades were analyzed individually and as combined CA12 and histologic grade categories for effects on survival outcome.
RESULTS: Immunohistochemical expression of CA12 was highly associated with the histologic grade of cervical cancer. Lack of CA12 expression was associated with PD histology, with an odds ratio of 3.9 (P = 0.01). Microarray analysis showed a fourfold reduction in CA12 gene expression in PD tumors. CA12 expression was marginally associated with superior disease-free survival. Application of the new combined categories resulted in further discrimination of the prognosis of patients with moderate and poorly differentiated tumor grade.
CONCLUSIONS: Our study indicates that CA12 may be used as a novel prognostic marker in combination with histologic grade of the tumors.

Ilie MI, Hofman V, Ortholan C, et al.
Overexpression of carbonic anhydrase XII in tissues from resectable non-small cell lung cancers is a biomarker of good prognosis.
Int J Cancer. 2011; 128(7):1614-23 [PubMed] Related Publications
The pattern of protein expression in tumors is under the influence of nutrient stress, hypoxia and low pH, which determines the survival of neoplastic cells and the development of tumors. Carbonic anhydrase XII (CAXII) is a transmembrane enzyme that catalyzes the reversible hydration of cell-generated carbon dioxide into protons and bicarbonate. Hypoxic conditions activate its transcription and translation and enhanced expression is often present in several types of tumors. The aim of our study was to assess the prognostic significance of CAXII tumor tissues expression in patients with NSCLC. Five hundred fifty-five tumors were immunostained for CAXII on tissue microarrays (TMA) and the results were correlated with clinicopathological parameters and outcome of patients. CAXII overexpression was present in 105/555 (19%) cases and was associated with tumors of lower grade (p = 0.015) and histological type (p < 0.001), being significantly higher in squamous cell carcinoma. High CAXII expression correlated with better overall and disease-specific survival of patients with resectable NSCLC in univariate (p < 0.001) and multivariate survival analyses (p < 0.001). In conclusion, this is the first study demonstrating that a high CAXII tumor tissue expression evaluated on TMAs is related to a better outcome in a large series of patients with resectable NSCLC.

Hsieh MJ, Chen KS, Chiou HL, Hsieh YS
Carbonic anhydrase XII promotes invasion and migration ability of MDA-MB-231 breast cancer cells through the p38 MAPK signaling pathway.
Eur J Cell Biol. 2010; 89(8):598-606 [PubMed] Related Publications
Carbonic anhydrase (CA) XII, an extracellular enzyme involved in the regulation of the microenvironment acidity and tumor malignant phenotype, was originally identified as a protein overexpressed in some types of cancers, including breast cancer. However, the cellular function and mechanism of CAXII remained unclear. In this study, the effects of CAXII expression on invasion and migration of breast cancer cells was investigated. Gene knockdown of CAXII in the human breast cancer cell line MDA-MB-231 resulted in decreased invasion and migration by interfering with the p38 MAPK pathway. CAXII knockdown also decreased the expression of matrix metalloproteinase (MMP)-2, MMP-9, and urokinase-type plasminogen activator (u-PA), but increased tissue inhibitor of metalloproteinases (TIMP)-2 and plasminogen activator inhibitor (PAI)-1 expression. Furthermore, decreased invasive and migration ability of CAXII-knockdown cells were restored by an overexpression of CAXII. Results also showed that CAXII knockdown may decrease anchorage-independent growth and cell growth by inhibiting CDK6 and cyclin D1 expression. Furthermore, the impact of CAXII knockdown on invasion, migration and cell growth was further evidenced by effects on tumor size and metastasis of MDA-MB-231 cells in vivo. Taken together, these data suggested that CAXII may affect the capability of invasion and migration of MDA-MB-231 cells, which may be mediated through the p38 MAPK pathway.

Davidson B, Stavnes HT, Holth A, et al.
Gene expression signatures differentiate ovarian/peritoneal serous carcinoma from breast carcinoma in effusions.
J Cell Mol Med. 2011; 15(3):535-44 [PubMed] Free Access to Full Article Related Publications
Ovarian/primary peritoneal carcinoma and breast carcinoma are the gynaecological cancers that most frequently involve the serosal cavities.With the objective of improving on the limited diagnostic panel currently available for the differential diagnosis of these two malignancies,as well as to define tumour-specific biological targets, we compared their global gene expression patterns. Gene expression profiles of 10 serous ovarian/peritoneal and eight ductal breast carcinoma effusions were analysed using the HumanRef-8 BeadChip from Illumina.Differentially expressed candidate genes were validated using quantitative real-time PCR and immunohistochemistry. Unsupervised hierarchical clustering using all 54,675 genes in the array separated ovarian from breast carcinoma samples. We identified 288 unique probes that were significantly differentially expressed in the two cancers by greater than 3.5-fold, of which 81 and 207 were overexpressed in breast and ovarian/peritoneal carcinoma, respectively. SAM analysis identified 1078 differentially expressed probes with false discovery rate less than 0.05. Genes overexpressed in breast carcinoma included TFF1, TFF3, FOXA1, CA12, GATA3, SDC1, PITX1, TH, EHFD1, EFEMP1, TOB1 and KLF2. Genes overexpressed in ovarian/peritoneal carcinoma included SPON1, RBP1, MFGE8, TM4SF12, MMP7, KLK5/6/7, FOLR1/3,PAX8, APOL2 and NRCAM. The differential expression of 14 genes was validated by quantitative real-time PCR, and differences in 5 gene products were confirmed by immunohistochemistry. Expression profiling distinguishes ovarian/peritoneal carcinoma from breast carcinoma and identifies genes that are differentially expressed in these two tumour types. The molecular signatures unique to these cancers may facilitate their differential diagnosis and may provide a molecular basis for therapeutic target discovery.

Stein L, Rothschild J, Luce J, et al.
Copy number and gene expression alterations in radiation-induced papillary thyroid carcinoma from chernobyl pediatric patients.
Thyroid. 2010; 20(5):475-87 [PubMed] Related Publications
BACKGROUND: Following exposure to radiation during the Chernobyl fallout tragedy, papillary thyroid carcinoma (PTC) increased significantly in individuals who were children at the time of the accident. We have used two high-throughput, whole genome platforms to analyze radiation-induced PTCs from pediatric patients from the Chernobyl region.
METHODS: We performed comparative genomic hybridization using Affymetrix 50K Mapping arrays and gene expression profiling on 10 pediatric post-Chernobyl PTCs obtained from patients living in the region. We performed an overlay analysis of these two data sets.
RESULTS: Many regions of copy number alterations (CNAs) were detected including novel regions that had never been associated with PTCs. Increases in copy numbers were consistently found on chromosomes 1p, 5p, 9q, 12q, 13q, 16p, 21q, and 22q. Deletions were observed less frequently and were mapped to 1q, 6q, 9q, 10q, 13q, 14q, 21q, and 22q. Gene expression analysis revealed that most of the altered genes were also perturbed in sporadic adult PTC; however, 141 gene expression changes were found to be unique to the post-Chernobyl tumors. The genes with the highest increases in expression that were novel to the pediatric post-Chernobyl tumors were TESC, PDZRN4, TRAa/TRDa, GABBR2, and CA12. The genes showing the largest expression decreases included PAPSS2, PDLIM3, BEXI, ANK2, SORBS2, and PPARGCIA. An overlay analysis of the gene expression and CNA profiles was then performed. This analysis identified genes showing both CNAs and concurrent gene expression alterations. Many of these are commonly seen in sporadic PTC such as SERPINA, COL8A, and PDX, while others were unique to the radiation-induced profiles including CAMK2N1, AK1, DHRS3, and PDE9A.
CONCLUSIONS: This type of analysis allows an assessment of gene expression changes that are associated with a physical mechanism. These genes and chromosomal regions are potential markers for radiation-induced PTC.

Li Y, Wang H, Oosterwijk E, et al.
Expression and activity of carbonic anhydrase IX is associated with metabolic dysfunction in MDA-MB-231 breast cancer cells.
Cancer Invest. 2009; 27(6):613-23 [PubMed] Free Access to Full Article Related Publications
The expression of carbonic anhydrase IX (CAIX), a marker for hypoxic tumors, is correlated with poor prognosis in breast cancer patients. We show herein that the MDA-MB-231 cells, a "triple-negative," basal B line, express exclusively CAIX, while a luminal cell line (T47D) expresses carbonic anhydrase XII (CAXII). CAIX expression in the basal B cells is both density- and hypoxia-dependent and is correlated with carbonic anhydrase activity. Evidence is provided that CAIX contributes to extracellular acidification through studies on pH, lactic acid production, and CAIX inhibition. Together, these studies suggest that CAIX expression and activity is associated with metabolic dysfunction in MDA-MB-231 cells.

Cheong SC, Chandramouli GV, Saleh A, et al.
Gene expression in human oral squamous cell carcinoma is influenced by risk factor exposure.
Oral Oncol. 2009; 45(8):712-9 [PubMed] Related Publications
Oral squamous cell carcinoma (OSCC) is a world health problem and is associated with exposure to different risk factors. In the west, smoking and alcohol consumption are considered to be the main risk factors whilst in India and southeast Asia, betel quid (BQ) chewing is predominant. In this study, we compared the gene expression patterns of oral cancers associated with BQ chewing to those caused by smoking using Affymetrix microarrays. We found that 281 genes were differentially expressed between OSCC and normal oral mucosa regardless of aetiological factors including MMP1, PLAU, MAGE-D4, GNA12, IFITM3 and NMU. Further, we identified 168 genes that were differentially expressed between the BQ and smoking groups including CXCL-9, TMPRSS2, CA12 and RNF24. The expression of these genes was validated using qPCR using independent tissue samples. The results demonstrate that whilst common genes/pathways contribute to the development of oral cancer, there are also other gene expression changes that are specific to certain risk factors. The findings suggest that different carcinogens activate or inhibit specific pathways during cancer development and progression. These unique gene expression profiles should be taken into consideration when developing biomarkers for future use in prognostic or therapeutic applications.

Barnett DH, Sheng S, Charn TH, et al.
Estrogen receptor regulation of carbonic anhydrase XII through a distal enhancer in breast cancer.
Cancer Res. 2008; 68(9):3505-15 [PubMed] Related Publications
The expression of carbonic anhydrase XII (CA12), a gene that encodes a zinc metalloenzyme responsible for acidification of the microenvironment of cancer cells, is highly correlated with estrogen receptor alpha (ER alpha) in human breast tumors. Here, we show that CA12 is robustly regulated by estrogen via ER alpha in breast cancer cells, and that this regulation involves a distal estrogen-responsive enhancer region. Upon the addition of estradiol, ER alpha binds directly to this distal enhancer in vivo, resulting in the recruitment of RNA polymerase II and steroid receptor coactivators SRC-2 and SRC-3, and changes in histone acetylation. Mutagenesis of an imperfect estrogen-responsive element within this enhancer region abolishes estrogen-dependent activity, and chromosome conformation capture and chromatin immunoprecipitation assays show that this distal enhancer communicates with the transcriptional start site of the CA12 gene via intrachromosomal looping upon hormone treatment. This distal enhancer element is observed in the homologous mouse genomic sequence, and the expression of the mouse homologue, Car12, is rapidly and robustly stimulated by estradiol in the mouse uterus in vivo, suggesting that the ER regulation of CA12 is mechanistically and evolutionarily conserved. Our findings highlight the crucial role of ER in the regulation of the CA12 gene, and provide insight into the transcriptional regulatory mechanism that accounts for the strong association of CA12 and ER in human breast cancers.

Scrideli CA, Carlotti CG, Okamoto OK, et al.
Gene expression profile analysis of primary glioblastomas and non-neoplastic brain tissue: identification of potential target genes by oligonucleotide microarray and real-time quantitative PCR.
J Neurooncol. 2008; 88(3):281-91 [PubMed] Related Publications
The prognosis of glioblastomas is still extremely poor and the discovery of novel molecular therapeutic targets can be important to optimize treatment strategies. Gene expression analyses comparing normal and neoplastic tissues have been used to identify genes associated with tumorigenesis and potential therapeutic targets. We have used this approach to identify differentially expressed genes between primary glioblastomas and non-neoplastic brain tissues. We selected 20 overexpressed genes related to cell cycle, cellular movement and growth, proliferation and cell-to-cell signaling and analyzed their expression levels by real time quantitative PCR in cDNA obtained from microdissected fresh tumor tissue from 20 patients with primary glioblastomas and from 10 samples of non-neoplastic white matter tissue. The gene expression levels were significantly higher in glioblastomas than in non-neoplastic white matter in 18 out of 20 genes analyzed: P < 0.00001 for CDKN2C, CKS2, EEF1A1, EMP3, PDPN, BNIP2, CA12, CD34, CDC42EP4, PPIE, SNAI2, GDF15 and MMP23b; and NFIA (P: 0.0001), GPS1 (P: 0.0003), LAMA1 (P: 0.002), STIM1 (P: 0.006), and TASP1 (P: 0.01). Five of these genes are located in contiguous loci at 1p31-36 and 2 at 17q24-25 and 8 of them encode surface membrane proteins. PDPN and CD34 protein expression were evaluated by immunohistochemistry and they showed concordance with the PCR results. The present results indicate the presence of 18 overexpressed genes in human primary glioblastomas that may play a significant role in the pathogenesis of these tumors and that deserve further functional investigation as attractive candidates for new therapeutic targets.

Chao A, Wang TH, Lai CH
Overview of microarray analysis of gene expression and its applications to cervical cancer investigation.
Taiwan J Obstet Gynecol. 2007; 46(4):363-73 [PubMed] Related Publications
Cervical cancer is one of the leading female cancers in Taiwan and ranks as the fifth cause of cancer death in the female population. Human papillomavirus has been established as the causative agent for cervical neoplasia and cervical cancer. However, the tumor biology involved in the prognoses of different cell types in early cancers and tumor responses to radiation in advanced cancers remain largely unknown. The introduction of microarray technologies in the 1990s has provided genome-wide strategies for searching tens of thousands of genes simultaneously. In this review, we first summarize the two types of microarrays: oligonucleotides microarray and cDNA microarray. Then, we review the studies of functional genomics in cervical cancer. Gene expression studies that involved cervical cancer cell lines, cervical cells of cancer versus normal ectocervix, cancer tissues of different histology, radioresistant versus radiosensitive patients, and the combinatorial gene expression associated with chromosomal amplifications are discussed. In particular, CEACAM5 , TACSTD1 , S100P , and MSLN have shown to be upregulated in adenocarcinoma, and increased expression levels of CEACAM5 and TACSTD1 were significantly correlated with poorer patient outcomes. On the other hand, 35 genes, including apoptotic genes (e.g. BIK , TEGT , SSI-3 ), hypoxia-inducible genes (e.g. HIF1A , CA12 ), and tumor cell invasion and metastasis genes (e.g. CTSL , CTSB , PLAU , CD44 ), have been noted to echo the hypothesis that increased tumor hypoxia leads to radiation resistance in cervical cancer during radiation.

Klatte T, Seligson DB, Riggs SB, et al.
Hypoxia-inducible factor 1 alpha in clear cell renal cell carcinoma.
Clin Cancer Res. 2007; 13(24):7388-93 [PubMed] Related Publications
PURPOSE: Hypoxia-inducible factor-1 alpha (HIF-1 alpha) plays an important role in tumoral adaptation to hypoxic conditions by serving as a transcription factor for several crucial proteins, including vascular endothelial growth factor and carbonic anhydrase IX (CAIX). Here, we evaluated the significance of HIF-1 alpha in renal cell carcinoma (RCC).
EXPERIMENTAL DESIGN: Immunohistochemical analysis was done on a tissue microarray constructed from paraffin-embedded primary tumor specimens from 357 patients treated by nephrectomy for RCC. Nuclear expression was evaluated by a single pathologist who was blinded to outcome. The expression levels were associated with pathologic variables and survival.
RESULTS: HIF-1 alpha expression was greater in RCC than in benign tissue. Clear cell RCC showed the highest expression levels. In clear cell RCC, HIF-1 alpha was significantly correlated with markers of apoptosis (p21, p53), the mammalian target of rapamycin pathway (pAkt, p27), CXCR3, and proteins of the vascular endothelial growth factor family. HIF-1 alpha was correlated with CAIX and CAXII in localized, but not in metastatic RCC. HIF-1 alpha expression predicted outcome in metastatic patients: patients with high HIF-1 alpha expression (>35%) had significantly worse survival than patients with low expression (< or =35%); median survival, 13.5 versus 24.4 months, respectively (P = 0.005). Multivariate analysis retained HIF-1 alpha and CAIX expression as the strongest independent prognostic factors for patients with metastatic clear cell RCC.
CONCLUSIONS: HIF-1 alpha is an important independent prognostic factor for patients with metastatic clear cell RCC. Because HIF-1 alpha and CAIX are independently and differentially regulated in metastatic clear cell RCC, both tumor markers can be complementary in predicting prognosis.

Lee S, Shin HJ, Han IO, et al.
Tumor carbonic anhydrase 9 expression is associated with the presence of lymph node metastases in uterine cervical cancer.
Cancer Sci. 2007; 98(3):329-33 [PubMed] Related Publications
Tumor hypoxia has a pronounced effect on malignant progression and metastatic spread of human tumors. As carbonic anhydrases (CA) 9 and 12 are induced by the low-oxygen environment within tumors, we investigated the relationship between the expression of these two CA and the presence of metastatic lymph nodes (LN) in uterine cervical cancer. CA9/CA12 expression was evaluated histochemically in primary cervical cancer tissues of 73 patients who underwent laparoscopic LN staging and two patients with clinical staging before definitive radiotherapy at the National Cancer Center, Korea. We also evaluated CA9 expression in 33 patients with pathologically confirmed metastatic LN. CA9 expression in the primary tumors was significantly associated with LN metastasis (P = 0.03) and poorer disease-free survival (relative risk, 6.1; 95% confidence interval, 1.3-28.3, P = 0.02, multivariate analysis), whereas CA12 expression did not show such a relationship. In addition, 21 of 24 metastatic LN revealed similar CA9 expression (P = 0.001), suggesting that CA9-expressing tumor cells had a higher metastatic potential. CA9 was expressed in 45 of 75 (60%) primary tumors, with positive tumor cells observed predominantly in the area away from the blood vessels. In contrast, CA12 expression was observed in only 29 of 74 primary tumors (39%), without a specific pattern. These findings indicate that expression of CA9, but not CA12, in tumors is associated with the presence of LN metastases and poorer prognosis. Selective application of new treatment modalities based on CA9 expression to prevent LN metastases may improve overall treatment outcome in patients with uterine cervical cancer.

Tozlu S, Girault I, Vacher S, et al.
Identification of novel genes that co-cluster with estrogen receptor alpha in breast tumor biopsy specimens, using a large-scale real-time reverse transcription-PCR approach.
Endocr Relat Cancer. 2006; 13(4):1109-20 [PubMed] Related Publications
The estrogen receptor alpha (ERalpha) plays a critical role in the pathogenesis and clinical behavior of breast cancer. To obtain further insights into the molecular basis of estrogen-dependent forms of this malignancy, we used real-time quantitative reverse transcription (RT)-PCR to compare the mRNA expression of 560 selected genes in ERalpha-positive and ERalpha-negative breast tumors. Fifty-one (9.1%) of the 560 genes were significantly upregulated in ERalpha-positive breast tumors compared with ERalpha-negative breast tumors. In addition to well-known ERalpha-induced genes (PGR, TFF1/PS2, BCL2, ERBB4, CCND1, etc.) and genes recently identified by cDNA microarray-based approaches (GATA3, TFF3, MYB, STC2, HPN/HEPSIN, FOXA1, XBP1, SLC39A6/LIV-1, etc.), an appreciable number of novel genes were identified, many of, which were weakly expressed. This validates the use of large-scale real-time RT-PCR as a method complementary to cDNA microarrays for molecular tumor profiling. Most of the new genes identified here encoded secreted proteins (SEMA3B and CLU), growth factors (BDNF, FGF2 and EGF), growth factor receptors (IL6ST, PTPRT, RET, VEGFR1 and FGFR2) or metabolic enzymes (CYP2B6, CA12, ACADSB, NAT1, LRBA, SLC7A2 and SULT2B1). Importantly, we also identified a large number of genes encoding proteins with either pro-apoptotic (PUMA, NOXA and TATP73) or anti-apoptotic properties (BCL2, DNTP73 and TRAILR3). Surprisingly, only a small proportion of the 51 genes identified in breast tumor biopsy specimens were confirmed to be ERalpha-regulated and/or E2-regulated in vitro (cultured cell lines). Therefore, this study identified a limited number of genes and signaling pathways, which better delineate the role of ERalpha in breast cancer. Some of the genes identified here could be useful for diagnosis or for predicting endocrine responsiveness, and could form the basis for novel therapeutic strategies.

Fryknäs M, Wickenberg-Bolin U, Göransson H, et al.
Molecular markers for discrimination of benign and malignant follicular thyroid tumors.
Tumour Biol. 2006; 27(4):211-20 [PubMed] Related Publications
OBJECTIVE: To identify molecular markers useful for the diagnostic discrimination of benign and malignant follicular thyroid tumors.
METHODS: A panel of thyroid tumors was characterized with expression profiling using cDNA microarrays. A robust algorithm for gene selection was developed to identify molecular markers useful for the classification of heterogeneous tumor classes. The study included tumor tissue specimens from 10 patients with benign follicular adenomas and from 10 with malignant tumors. The malignant tumors mainly consisted of clinically relevant minimally invasive follicular carcinomas. The mRNA expression level of a candidate gene, FHL1, was evaluated in an independent series of 61 tumors.
RESULTS: 22 gene expression markers were identified as differentially expressed. Several of the identified genes, for example DIO1, CITED1, CA12 and FN1, have previously been observed as differentially expressed in various thyroid tumors. FHL1 was significantly underexpressed in carcinomas compared to adenomas in the independent panel of tumors. The results indicate that a small number of genes can be useful to distinguish follicular adenomas from follicular carcinomas.
CONCLUSIONS: Our findings clearly corroborate previous studies and identify novel candidate molecular markers. These genes have the potential for molecular classification of follicular thyroid tumors and for providing improved understanding of the molecular mechanisms involved in thyroid malignancies.

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