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• W2141217856 abstract "Carbonic anhydrases (CA) influence intra- and extracellular pH and ion transport in varied biological processes. We recently identified CA9 and CA12 as hypoxia-inducible genes. In this study we examined the expression of these tumor-associated CAs by immunohistochemistry in relation to necrosis and early breast tumor progression in 68 cases of ductal carcinoma in situ (DCIS) (39 pure DCIS and 29 DCIS associated with invasive carcinoma). CA IX expression was rare in normal epithelium and benign lesions, but was present focally in DCIS (50% of cases) and in associated invasive carcinomas (29%). In comparison, CA XII was frequently expressed in normal breast tissues (89%), in DCIS (84%), and in invasive breast lesions (71%). In DCIS, CA IX was associated with necrosis (P= 0.0053) and high grade (P = 0.012). In contrast, CA XII was associated with the absence of necrosis (P = 0.036) and low grade (P = 0.012). Despite this, augmented CA XII expression was occasionally observed adjacent to necrosis within high-grade lesions. Neither CA IX nor CA XII expression was associated with regional or overall proliferation as determined by MIB1 staining. Assessment of mammographic calcification showed that CA XII expression was associated with the absence of calcification (n = 43, P = 0.0083). Our results demonstrate that induction of CA IX and CA XII occurs in regions adjacent to necrosis in DCIS. Furthermore, these data suggest that proliferation status does not influence expression of either CA in breast tissues, that hypoxia may be a dominant factor in the regulation of CA IX, and that factors related to differentiation, as determined by tumor grade, dominate the regulation of CA XII. The existence of differential regulation and associations with an aggressive phenotype may be important in the development of selective inhibitors of CAs, because the latter have recently been shown to prevent tumor invasion. Carbonic anhydrases (CA) influence intra- and extracellular pH and ion transport in varied biological processes. We recently identified CA9 and CA12 as hypoxia-inducible genes. In this study we examined the expression of these tumor-associated CAs by immunohistochemistry in relation to necrosis and early breast tumor progression in 68 cases of ductal carcinoma in situ (DCIS) (39 pure DCIS and 29 DCIS associated with invasive carcinoma). CA IX expression was rare in normal epithelium and benign lesions, but was present focally in DCIS (50% of cases) and in associated invasive carcinomas (29%). In comparison, CA XII was frequently expressed in normal breast tissues (89%), in DCIS (84%), and in invasive breast lesions (71%). In DCIS, CA IX was associated with necrosis (P= 0.0053) and high grade (P = 0.012). In contrast, CA XII was associated with the absence of necrosis (P = 0.036) and low grade (P = 0.012). Despite this, augmented CA XII expression was occasionally observed adjacent to necrosis within high-grade lesions. Neither CA IX nor CA XII expression was associated with regional or overall proliferation as determined by MIB1 staining. Assessment of mammographic calcification showed that CA XII expression was associated with the absence of calcification (n = 43, P = 0.0083). Our results demonstrate that induction of CA IX and CA XII occurs in regions adjacent to necrosis in DCIS. Furthermore, these data suggest that proliferation status does not influence expression of either CA in breast tissues, that hypoxia may be a dominant factor in the regulation of CA IX, and that factors related to differentiation, as determined by tumor grade, dominate the regulation of CA XII. The existence of differential regulation and associations with an aggressive phenotype may be important in the development of selective inhibitors of CAs, because the latter have recently been shown to prevent tumor invasion. The management of pre-invasive ductal carcinoma in situ (DCIS) of the breast has become an increasingly significant problem. This is due in part to both the increasing number of these lesions detected by mammography,1Ernster VL Barclay J Kerlikowske K Grady D Henderson C Incidence of and treatment for ductal carcinoma in situ of the breast.JAMA. 1996; 275: 913-918Crossref PubMed Google Scholar, 2Ernster VL Barclay J Increases in ductal carcinoma in situ (DCIS) of the breast in relation to mammography: a dilemma.J Natl Cancer Inst Monogr. 1997; 22: 151-156PubMed Google Scholar and the impetus provided by the demonstration that invasive breast cancer may be delayed or inhibited by tamoxifen therapy in women at high risk.3Fentiman IS Trials of treatment for non-invasive breast cancer.Recent Results Cancer Res. 1998; 152: 135-142Crossref PubMed Scopus (6) Google Scholar, 4Fisher B Highlights from recent National Surgical Adjuvant Breast and Bowel Project studies in the treatment and prevention of breast cancer.CA Cancer J Clin. 1999; 49: 159-177Crossref PubMed Scopus (50) Google Scholar Assessment of DCIS and the risk of progression to invasive disease is complicated by the small size and focal nature of most breast lesions, and has traditionally been based primarily on morphological classification and grading of pre-invasive disease by the pattern of growth into comedo and noncomedo subtypes. Recently, radiological studies have suggested that abnormal patterns of calcification may be associated with high-grade DCIS,5Holland R Hendriks JH Microcalcifications associated with ductal carcinoma in situ: mammographic-pathologic correlation.Semin Diagn Pathol. 1994; 11: 181-192PubMed Google Scholar, 6Tabar L Chen HH Duffy SW Yen MF Chiang CF Dean PB Smith RA A novel method for prediction of long-term outcome of women with T1a, T1b, and 10–14 mm invasive breast cancers: a prospective study.Lancet. 2000; 355: 429-433Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar whereas pathological studies have developed more reproducible and discriminating schema for classification of DCIS lesions.7Shoker BS Sloane JP DCIS grading schemes and clinical implications.Histopathology. 1999; 35: 393-400Crossref PubMed Scopus (48) Google Scholar Consequently, the presence of necrosis and nuclear grade8Fisher ER Costantino J Fisher B Palekar AS Redmond C Mamounas E Pathologic findings from the National Surgical Adjuvant Breast Project (NSABP) Protocol B-17. Intraductal carcinoma (ductal carcinoma in situ). The National Surgical Adjuvant Breast and Bowel Project Collaborating Investigators.Cancer. 1995; 75: 1310-1319Crossref PubMed Scopus (348) Google Scholar, 9Silverstein MJ Lagios MD Craig PH Waisman JR Lewinsky BS Colburn WJ Poller DN A prognostic index for ductal carcinoma in situ of the breast.Cancer. 1996; 77: 2267-2274Crossref PubMed Scopus (660) Google Scholar have emerged as important aspects to consider when assessing breast lesions, although consistent recognition and quantification of both parameters remains problematic.10Schnitt SJ Harris JR Smith BL Developing a prognostic index for ductal carcinoma in situ of the breast. Are we there yet?.Cancer. 1996; 77: 2189-2192Crossref PubMed Scopus (64) Google Scholar Necrosis is believed to represent the extreme manifestation of hypoxia within tissues.11Leek RD Landers RJ Harris AL Lewis CE Necrosis correlates with high vascular density and focal macrophage infiltration in invasive carcinoma of the breast.Br J Cancer. 1999; 79: 991-995Crossref PubMed Scopus (395) Google Scholar Interestingly, tumor hypoxia has been shown to be a prognostic indicator for many tumor types, being associated with aggressive growth, metastasis, and poor response to treatment not only in patients treated with radiotherapy, but also in those treated with surgery alone.12Wetzels RH Kuijpers HJ Lane EB Leigh IM Troyanovsky SM Holland R van Haelst UJ Ramaekers FC Basal cell-specific and hyperproliferation-related keratins in human breast cancer.Am J Pathol. 1991; 138: 751-763PubMed Google Scholar, 13Vaupel P Hoeckel M Predictive power of the tumor oxygenation status.Adv Exp Med Biol. 1999; 471: 533-539Crossref PubMed Google Scholar, 14Dachs GU Chaplin DJ Microenvironmental control of gene expression: implications for tumor angiogenesis, progression, and metastasis.Semin Radiat Oncol. 1998; 8: 208-216Abstract Full Text PDF PubMed Scopus (92) Google Scholar, 15Brizel DM Sibley GS Prosnitz LR Scher RL Dewhirst MW Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck.Int J Radiat Oncol Biol Phys. 1997; 38: 285-289Abstract Full Text PDF PubMed Scopus (971) Google Scholar, 16Walenta S Wetterling M Lehrke M Schwickert G Sundfor K Rofstad EK Mueller-Klieser W High lactate levels predict likelihood of metastases, tumor recurrence, and restricted patient survival in human cervical cancers.Cancer Res. 2000; 60: 916-921PubMed Google Scholar Of potential importance for understanding these effects is the role of hypoxia in regulating patterns of gene expression. Studies of gene expression have defined several classes of genes that are up-regulated by hypoxia and demonstrated that activation of the transcriptional complex hypoxia-inducible factor-1 is a key mediator of many of these effects.17Maxwell PH Dachs GU Gleadle JM Nicholls LG Harris AL Stratford IJ Hankinson O Pugh CW Ratcliffe PJ Hypoxia-inducible factor-1 modulates gene expression in solid tumors and influences both angiogenesis and tumor growth.Proc Natl Acad Sci USA. 1997; 94: 8104-8109Crossref PubMed Scopus (951) Google Scholar, 18Zhong H De Marzo AM Laughner E Lim M Hilton DA Zagzag D Buechler P Isaacs WB Semenza GL Simons JW Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases.Cancer Res. 1999; 59: 5830-5835PubMed Google Scholar Genes that are up-regulated by microenvironmental hypoxia through hypoxia-inducible factor-1 activation include glucose transporters, glycolytic enzymes, and angiogenic growth factors. We recently identified the two tumor-associated transmembrane carbonic anhydrases (CA) CA919Grabmaier K Vissers JL De Weijert MC Oosterwijk-Wakka JC Van Bokhoven A Brakenhoff RH Noessner E Mulders PA Merkx G Figdor CG Adema GJ Oosterwijk E Molecular cloning and immunogenicity of renal cell carcinoma-associated antigen G250.Int J Cancer. 2000; 85: 865-870Crossref PubMed Scopus (156) Google Scholar, 20Ivanov SV Kuzmin I Wei MH Pack S Geil L Johnson BE Stanbridge EJ Lerman MI Down-regulation of transmembrane carbonic anhydrases in renal cell carcinoma cell lines by wild-type von Hippel-Lindau transgenes.Proc Natl Acad Sci USA. 1998; 95: 12596-12601Crossref PubMed Scopus (341) Google Scholar, 21Opavsky R Pastorekova S Zelnik V Gibadulinova A Stanbridge EJ Zavada J Kettmann R Pastorek J Human MN/CA9 gene, a novel member of the carbonic anhydrase family: structure and exon to protein domain relationships.Genomics. 1996; 33: 480-487Crossref PubMed Scopus (333) Google Scholar and CA1220Ivanov SV Kuzmin I Wei MH Pack S Geil L Johnson BE Stanbridge EJ Lerman MI Down-regulation of transmembrane carbonic anhydrases in renal cell carcinoma cell lines by wild-type von Hippel-Lindau transgenes.Proc Natl Acad Sci USA. 1998; 95: 12596-12601Crossref PubMed Scopus (341) Google Scholar, 22Tureci O Sahin U Vollmar E Siemer S Gottert E Seitz G Parkkila AK Shah GN Grubb JH Pfreundschuh M Sly WS Human carbonic anhydrase XII: cDNA cloning, expression, and chromosomal localization of a carbonic anhydrase gene that is overexpressed in some renal cell cancers.Proc Natl Acad Sci USA. 1998; 95: 7608-7613Crossref PubMed Scopus (323) Google Scholar as being up-regulated by hypoxia in epithelial tumor cell lines.23Wykoff C Beasley NJP Watson PH Turner KJ Pastorek J Sibtain A Wilson GD Turley H Talks K Maxwell PH Pugh CW Ratcliffe PJ Harris AL Hypoxia inducible expression of tumor associated carbonic anhydrases.Cancer Res. 2000; 60: 7075-7083PubMed Google Scholar Furthermore, we demonstrated focal perinecrotic expression of CA IX in invasive human tumors, co-localizing with vascular endothelial growth factor mRNA expression and pimonidazole activation.23Wykoff C Beasley NJP Watson PH Turner KJ Pastorek J Sibtain A Wilson GD Turley H Talks K Maxwell PH Pugh CW Ratcliffe PJ Harris AL Hypoxia inducible expression of tumor associated carbonic anhydrases.Cancer Res. 2000; 60: 7075-7083PubMed Google Scholar CA9 and CA12 are members of a family of catalytically active CAs that share the capacity to catalyze the reversible hydration of carbon dioxide to carbonic acid.24Jiang W Gupta D Structure of the carbonic anhydrase VI (CA6) gene: evidence for two distinct groups within the alpha-CA gene family.Biochem J. 1999; 344: 385-390Crossref PubMed Scopus (17) Google Scholar CA IX19Grabmaier K Vissers JL De Weijert MC Oosterwijk-Wakka JC Van Bokhoven A Brakenhoff RH Noessner E Mulders PA Merkx G Figdor CG Adema GJ Oosterwijk E Molecular cloning and immunogenicity of renal cell carcinoma-associated antigen G250.Int J Cancer. 2000; 85: 865-870Crossref PubMed Scopus (156) Google Scholar, 21Opavsky R Pastorekova S Zelnik V Gibadulinova A Stanbridge EJ Zavada J Kettmann R Pastorek J Human MN/CA9 gene, a novel member of the carbonic anhydrase family: structure and exon to protein domain relationships.Genomics. 1996; 33: 480-487Crossref PubMed Scopus (333) Google Scholar, 25Pastorek J Pastorekova S Callebaut I Mornon JP Zelnik V Opavsky R Zat'ovicova M Liao S Portetelle D Stanbridge EJ Cloning and characterization of MN, a human tumor-associated protein with a domain homologous to carbonic anhydrase and a putative helix-loop-helix DNA binding segment.Oncogene. 1994; 9: 2877-2888PubMed Google Scholar has been studied extensively in several tumor types including lung, kidney, colon, and cervix, where its expression has been established as a marker of cellular proliferation and early dysplasia.26Nogradi A The role of carbonic anhydrases in tumors.Am J Pathol. 1998; 153: 1-4Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar, 27Liao SY Stanbridge EJ Expression of the MN antigen in cervical Papanicolaou smears is an early diagnostic biomarker of cervical dysplasia.Cancer Epidemiol Biomarkers Prev. 1996; 5: 549-557PubMed Google Scholar, 28Liao SY Aurelio ON Jan K Zavada J Stanbridge EJ Identification of the MN/CA9 protein as a reliable diagnostic biomarker of clear cell carcinoma of the kidney.Cancer Res. 1997; 57: 2827-2831PubMed Google Scholar, 29Liao SY Stanbridge EJ Expression of MN/CA9 protein in Papanicolaou smears containing atypical glandular cells of undetermined significance is a diagnostic biomarker of cervical dysplasia and neoplasia.Cancer. 2000; 88: 1108-1121Crossref PubMed Scopus (32) Google Scholar, 30Vermylen P Roufosse C Burny A Verhest A Bosschaerts T Pastorekova S Ninane V Sculier JP Carbonic anhydrase IX antigen differentiates between preneoplastic malignant lesions in non-small cell lung carcinoma.Eur Respir J. 1999; 14: 806-811Crossref PubMed Scopus (86) Google Scholar CA XII was initially identified in renal carcinoma,22Tureci O Sahin U Vollmar E Siemer S Gottert E Seitz G Parkkila AK Shah GN Grubb JH Pfreundschuh M Sly WS Human carbonic anhydrase XII: cDNA cloning, expression, and chromosomal localization of a carbonic anhydrase gene that is overexpressed in some renal cell cancers.Proc Natl Acad Sci USA. 1998; 95: 7608-7613Crossref PubMed Scopus (323) Google Scholar and subsequently shown to be associated with colon carcinoma where altered expression occurs in early stages of tumorigenesis.31Kivela A Parkkila S Saarnio J Karttunen TJ Kivela J Parkkila AK Waheed A Sly WS Grubb JH Shah G Tureci O Rajaniemi H Expression of a novel transmembrane carbonic anhydrase isozyme XII in normal human gut and colorectal tumors.Am J Pathol. 2000; 156: 577-584Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar However, the expression of these CAs in breast cancer has not been examined. We investigated CA IX and CA XII expression in breast cancer in anticipation that their expression might serve as indicators of tissue hypoxia, altered pH, and tumor progression. Specifically we wished to assess the pattern of expression of these genes in DCIS, where the appearance of necrosis and abnormal calcification is associated with a high risk of progression to invasive disease. Sixty-eight pathological specimens containing DCIS of the breast were selected from review of surgical resections collected from 1997 to 1999 at the John Radcliffe Hospital and the Churchill Hospital, Oxford, UK. The cohort comprised 39 cases of pure DCIS (DCIS−) and 29 cases of DCIS associated with invasive carcinoma in the same biopsy (DCIS+), either independent from or directly associated with adjoining invasive carcinoma. All DCIS lesions were classified into histological grades on the basis of the predominant grade present in the tissue section studied for gene expression according to the Van Nuys grading system.9Silverstein MJ Lagios MD Craig PH Waisman JR Lewinsky BS Colburn WJ Poller DN A prognostic index for ductal carcinoma in situ of the breast.Cancer. 1996; 77: 2267-2274Crossref PubMed Scopus (660) Google Scholar, 32Silverstein MJ Poller DN Waisman JR Colburn WJ Barth A Gierson ED Lewinsky B Gamagami P Slamon DJ Prognostic classification of breast ductal carcinoma-in-situ.Lancet. 1995; 345: 1154-1157Crossref PubMed Scopus (619) Google Scholar The presence of intraductal necrosis within any component of DCIS within the tissue section was evaluated in hematoxylin and eosin-stained sections by light microscopy. The radiological appearance was classified according to the presence and pattern of calcification5Holland R Hendriks JH Microcalcifications associated with ductal carcinoma in situ: mammographic-pathologic correlation.Semin Diagn Pathol. 1994; 11: 181-192PubMed Google Scholar, 6Tabar L Chen HH Duffy SW Yen MF Chiang CF Dean PB Smith RA A novel method for prediction of long-term outcome of women with T1a, T1b, and 10–14 mm invasive breast cancers: a prospective study.Lancet. 2000; 355: 429-433Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar in preoperative mammograms for a subset of cases in which films were available (n = 43). These classifications were performed by a single pathologist (PHW) and radiologist (RE), respectively, without reference to the cohort’s immunohistochemical data and outcome. Among the series of cases, the histological grades were as follows: 18 low grade (8 DCIS−, 10 DCIS+), 24 intermediate grade (15 DCIS−, 9 DCIS+), and 26 high grade (16 DCIS−, 10 DCIS+). Intraductal necrosis was present in 51 cases (75%), among which 29 were DCIS− and 22 DCIS+. Mammographic calcifications were present in 35 of 43 cases, among which 27 of 35 were DCIS− and eight of 35 DCIS+. The pattern of calcification was classified as linear type (14 cases) if the presence of any linear calcification was seen, nonlinear type (21 cases), or absent (eight cases). MDA-MB-231 and ZR-75.1 cell lines were from ATCC (Rockville, MD). Hypoxic conditions were generated in a Napco 7001 incubator (Precision Scientific, Winchester, VA) with 0.1% O2, 5% CO2, and balance N2 for 16 hours. Whole-cell protein extracts were prepared from tissue culture cells by 10 seconds of homogenization in denaturing conditions as described.33Wiesener MS Turley H Allen WE Willam C Eckardt KU Talks KL Wood SM Gatter KC Harris AL Pugh CW Ratcliffe PJ Maxwell PH Induction of endothelial PAS domain protein-1 by hypoxia: characterization and comparison with hypoxia-inducible factor-1alpha.Blood. 1998; 92: 2260-2268Crossref PubMed Google Scholar Whole-cell protein extracts were prepared from tumors by fine section of frozen tissue and 30 seconds of homogenization in denaturing conditions identical to tissue-culture extracts. For Western analysis, aliquots were separated under reducing conditions by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and transferred to Immobilon-P membranes (Millipore, Hertfordshire, UK). CA IX was detected using the mouse monoclonal anti-human CA IX antibody M75 (1:50) as described.34Pastorekova S Zavadova Z Kostal M Babusikova O Zavada J A novel quasi-viral agent, MaTu, is a two-component system.Virology. 1992; 187: 620-626Crossref PubMed Scopus (272) Google Scholar CA XII was detected using a rabbit polyclonal anti-human CA XII antibody (1:2000) as described.22Tureci O Sahin U Vollmar E Siemer S Gottert E Seitz G Parkkila AK Shah GN Grubb JH Pfreundschuh M Sly WS Human carbonic anhydrase XII: cDNA cloning, expression, and chromosomal localization of a carbonic anhydrase gene that is overexpressed in some renal cell cancers.Proc Natl Acad Sci USA. 1998; 95: 7608-7613Crossref PubMed Scopus (323) Google Scholar horseradish peroxidase-conjugated goat-anti-mouse and swine anti-rabbit immunoglobulins (DAKO, Cambridgeshire, UK) (1:2000), respectively, were applied for 1 hour at room temperature. ECL Plus (Amersham Pharmacia, Buckinghamshire, UK) was used for visualization. Formalin-fixed, paraffin-embedded tissue specimens collected by standard surgical oncology procedures were obtained from the Pathology Department, John Radcliffe Hospital, Oxford, UK. Immunostaining of paraffin sections was performed after dewaxing and rehydrating 5-μm sections. Staining for CA IX, CA XII, and MIB1 was performed on serial sections. Endogenous peroxidase was blocked with 0.5% hydrogen peroxide in water for 30 minutes. Ten percent normal human serum in Tris-buffered saline was applied for 15 minutes at room temperature to block nonspecific protein binding. Primary antibodies: anti-human CA IX murine monoclonal antibody M75 (1:50);35Saarnio J Parkkila S Parkkila AK Haukipuro K Pastorekova S Pastorek J Kairaluoma MI Karttunen TJ Immunohistochemical study of colorectal tumors for expression of a novel transmembrane carbonic anhydrase, MN/CA IX, with potential value as a marker of cell proliferation.Am J Pathol. 1998; 153: 279-285Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar anti-human CA XII rabbit polyclonal antibody (1:2000); anti-human Ki67 murine monoclonal antibody MIB1 (1:50) (Immunotech). Primary antibodies were incubated for 30 minutes at room temperature in Tris-buffered saline with 5% normal human serum, followed by a 30-minute incubation with a peroxidase-conjugated secondary antibody. After each incubation, slides were washed twice with Tris-buffered saline for 5 minutes. Visualization of staining was by diaminobenzidine substrate for 8 minutes. Slides were counterstained with hematoxylin before mounting in Aquamount (BDH). Substitution of primary antibody with PBS was used as a negative control for each antibody. All staining was performed on an automated IHC stainer (MiniPrep 75; Tecan) at room temperature. Immunostaining for CA IX and CA XII was assessed by light microscopy and semiquantitative scoring was performed by a single pathologist (PHW), independently of the pathological assessment. Expression and intensity was scored (0, no staining; 1, weak staining; 2, moderate staining; and 3, strong staining), together with the percentage of normal or neoplastic epithelial cells showing expression within the tissue section (0 to 100%). The product of the intensity and the percentage gave a final immunostaining score (0 to 300; IHC score). MIB1 expression was assessed using a Chalkley point array method adapted from methods used to assess vascular density in breast sections.11Leek RD Landers RJ Harris AL Lewis CE Necrosis correlates with high vascular density and focal macrophage infiltration in invasive carcinoma of the breast.Br J Cancer. 1999; 79: 991-995Crossref PubMed Scopus (395) Google Scholar Briefly, MIB1-immunostained section was reviewed at low magnification and five areas showing the highest density of MIB1-positive tumor cells were selected. These hot spots were then assessed at higher magnification (×25 objective) and the number of grid points that coincided with positive and negative tumor cell nuclei was counted. The mean ratio of MIB1-positive/MIB1-negative cells was then calculated. Each hot spot contained between 200 and 1000 tumor cells depending on DCIS histology. The anti-CA IX and anti-CA XII antibodies used in this study have been previously characterized for immunostaining in many human tissues.22Tureci O Sahin U Vollmar E Siemer S Gottert E Seitz G Parkkila AK Shah GN Grubb JH Pfreundschuh M Sly WS Human carbonic anhydrase XII: cDNA cloning, expression, and chromosomal localization of a carbonic anhydrase gene that is overexpressed in some renal cell cancers.Proc Natl Acad Sci USA. 1998; 95: 7608-7613Crossref PubMed Scopus (323) Google Scholar, 31Kivela A Parkkila S Saarnio J Karttunen TJ Kivela J Parkkila AK Waheed A Sly WS Grubb JH Shah G Tureci O Rajaniemi H Expression of a novel transmembrane carbonic anhydrase isozyme XII in normal human gut and colorectal tumors.Am J Pathol. 2000; 156: 577-584Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar, 34Pastorekova S Zavadova Z Kostal M Babusikova O Zavada J A novel quasi-viral agent, MaTu, is a two-component system.Virology. 1992; 187: 620-626Crossref PubMed Scopus (272) Google Scholar, 36Saarnio J Parkkila S Parkkila AK Waheed A Casey MC Zhou XY Pastorekova S Pastorek J Karttunen T Haukipuro K Kairaluoma MI Sly WS Immunohistochemistry of carbonic anhydrase isozyme IX (MN/CA IX) in human gut reveals polarized expression in the epithelial cells with the highest proliferative capacity.J Histochem Cytochem. 1998; 46: 497-504Crossref PubMed Scopus (146) Google Scholar However, neither antibody has been applied extensively to breast specimens. Therefore, initial experiments were performed to compare IHC profiles with immunoblotting signals from a set of six invasive breast ductal carcinomas. By IHC, two cases exhibited strong membranous staining for CA IX that was restricted to the invasive ductal carcinoma cells, one was weakly positive, and three were negative (data not shown). Two of the tumors that were either negative or weakly positive for CA IX by IHC exhibited strong membranous staining for CA XII, whereas four cases were negative (data not shown). Immunoblotting for CA IX and CA XII was performed in parallel on protein lysates obtained from the same tumor specimens. As shown in Figure 1A, immunoblotting for CA IX revealed a 54- to 58-kd doublet restricted to the two cases that were strongly positive by IHC. Similarly, immunoblotting for CA XII revealed a 46- to 48-kd doublet restricted to the two cases that were positive by IHC. We have previously demonstrated wide-spread hypoxic induction of CA9 and CA12 mRNA in various tumor cell lines.23Wykoff C Beasley NJP Watson PH Turner KJ Pastorek J Sibtain A Wilson GD Turley H Talks K Maxwell PH Pugh CW Ratcliffe PJ Harris AL Hypoxia inducible expression of tumor associated carbonic anhydrases.Cancer Res. 2000; 60: 7075-7083PubMed Google Scholar Here we compared hypoxic induction of CA IX and CA XII in two breast cell lines selected as representative of estrogen receptor (ER)-negative and poorly differentiated (MDA-MB-231), and ER-positive and well-differentiated (ZR-75.1) breast cancer (Figure 1B). CA IX had an undetectable or low basal level of expression and was markedly induced by hypoxia. In comparison, CA XII had a higher level of normoxic expression and was further induced by hypoxia in one of the two cell lines. A series of 68 DCIS breast cases were studied for CA IX expression by IHC. Subsets of these cases also contained normal lobular and ductal components (n = 47), and invasive ductal carcinoma components (n = 29). CA IX expression was present in normal epithelium in one of 47 cases (2%), and in this case was limited to focal expression adjacent to the site of a recent biopsy. In many cases, benign breast lesions were present within the tissue section, including cystic changes, apocrine metaplasia, blunt duct, and sclerosis adenosis. No expression was observed in any benign breast lesion. In DCIS lesions, focal membranous CA IX staining, typically adjacent to areas of necrosis, was present in 34 of 68 (50%) cases, including 23 of 39 (59%) pure DCIS and 11 of 29 (38%) DCIS associated with invasive disease. In those cases in which invasive disease was present on the same tumor section, CA IX was expressed adjacent to regions of necrosis where this was present within the invasive component in four of 14 cases (29%). The presence of CA IX staining in both DCIS and invasive components was correlated (r = 0.55, P = 0.04). The focal perinecrotic nature of expression was reflected in the distribution of IHC scores with only 13 (19%) tumors scoring >10 (potential range of IHC score was 0 to 300, as described in Materials and Methods). The range of IHC scores was from 0 to 100 (median, 1; mean, 9; and SD, 17). Representative examples of low and high CA IX expression are illustrated in Figure 2, A and B. CA IX was significantly associated with high grade (grade low versus intermediate versus high; mean (SD), 2 (5), 11 (16), 13 (22), P = 0.012 analysis of variance) and the presence of necrosis (necrosis negative versus positive; mean (SD), 2 (5), 12 (19), P = 0.0053, Mann Whitney; Figure 3 and Table 1).Figure 3CA IX and CA XII expression are inversely related to grade and the presence of necrosis in DCIS. CA IX expression shown relative to grade (upper left) and necrosis (upper right) and CA XII expression shown relative to grade (lower left) and necrosis (lower right). Columns (CA IX, black; CA XII, hatched) represent the mean IHC score with bars showing SD relative to DCIS grade (low, intermediate, high) and necrosis (absent, present).View Large Image Figure ViewerDownload Hi-res image Download (PPT)Table 1Relationship between CA IX or CA XII Expression and Grade, Necrosis, and MIB1 StainingC" @default.
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• W2141217856 title "Expression of the Hypoxia-Inducible and Tumor-Associated Carbonic Anhydrases in Ductal Carcinoma in Situ of the Breast" @default.
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