Abstract
The cadherin-catenin system mediates Ca2+-dependent cell-cell adhesion, and genetic alterations in these molecules play a significant role in multistage carcinogenesis. Mutations in the β-catenin gene, mostly affecting exon 3, have been detected in malignant cell lines and in primary tumors. Immunohistochemical abnormalities in α-, β-, and γ-catenin have been reported in malignant and benign tumors, and nuclear localization of β-catenin has been associated with mutations in exon 3 of this gene.
Mutational analysis of exon 3 of the β-catenin gene was undertaken by polymerase chain reaction (PCR) and sequencing using genomic DNA extracted from frozen tissues, including 4 normal pituitaries, 22 pituitary adenomas, and one pituitary carcinoma. Frozen sections from these cases were used for immunohistochemical detection of β-catenin. We also analyzed immunohistochemical expression of α-, β-, and γ-catenin by paraffin sections from 154 pituitary tumors, including 148 adenomas and 6 carcinomas. Genomic DNA was extracted from paraffin sections of 2 gonadotroph tumors showing nuclear staining for β-catenin and was used for PCR and sequencing of exon 3 of the β-catenin gene.
No mutations in exon 3 of the β-catenin gene were found in any of the 23 cases analyzed by PCR and sequencing. In addition, the 2 cases studied by paraffin section immunohistochemistry, with nuclear staining for β-catenin, were negative for mutations in this exon. Normal pituitary expressed all three catenin proteins. Immunostaining usually showed a membranous pattern of reactivity and was generally stronger in normal pituitary than in the adjacent adenomas. Stains for α-catenin were positive in fewer tumors than for β-catenin. The lowest frequency immunopositive tumors and the weakest immunostaining was for γ-catenin. All medically treated prolactinomas were negative for γ-catenin, whereas treated growth hormone adenomas were less often positive for both α- and γ-catenin than for untreated tumors. The percentage of positive cases for β-catenin was the same in these two groups. Most pituitary carcinomas were negative for both α- and γ-catenin but were β-catenin positive.
These results indicate that (i) mutations in exon 3 of the β-catenin gene are uncommon in pituitary tumors, and (ii) expression of α-, β-, and γ-catenin is decreased in pituitary adenomas compared to normal pituitary tissues.
Similar content being viewed by others
References
Potter E, Bergwitz C, Brabant G. The cadherin-catenin system: implications for growth and differentiation of endocrine tissues. Endocr Rev 20:207–239, 1999.
Hirohashi S. Inactivation of the E-cadherin-mediated cell adhesion system in human cancers. Am J Pathol 153:333–339, 1998.
Cerrato A, Fulciniti F, Avallone A, Benincasa G, Palombini L, Grieco M. Beta- and gamma-catenin expression in thyroid carcinomas. J Pathol 185:267–272, 1998.
Huang SH, Wu JC, Chang KJ, Liaw KY, Wang SM. Expression of the cadherin-catenin complex in well-differentiated human thyroid neoplastic tissue. Thyroid 9:1095–1103, 1999.
Garcia-Rostan G, Tallini G, Herrero A, D’Aquila TG, Carcangiu ML, Rimm DL. Frequent mutation and nuclear localization of beta-catenin in anaplastic thyroid carcinoma. Cancer Res 59:1811–1815, 1999.
Heinrich CA, Lail-Trecker MR, Peluso JJ, White BA. Negative regulation of N-cadherin-mediated cell-cell adhesion by the estrogen receptor signaling pathway in rat pituitary GH3 cells. Endocrine 10:67–76, 1999.
Spangler PR, Delidow BC. Co-regulation of pituitary tumor cell adhesion and prolactin gene expression by glucocorticoid. J Cell Physiol 174:115–124, 1998.
Semba S, Han J-Y, Ikeda H, and Horii A. Frequent nuclear accumulation of beta-catenin in human pituitary adenoma. Cancer Cytopathol 91:42–48, 2001.
Aberle H, Bauer A, Stappert J, Kispert A, Kemler R. Beta-catenin is a target for the ubiquitin-proteasome pathway. EMBO J 16:3797–3804, 1997.
Behrens J, von Kries JP, Kuhl M, Bruhn L, Wedlich D, Grosschedl R, Birchmeier W. Functional interaction of beta-catenin with the transcription factor LEF-1. Nature 382:638–642, 1996.
Huber O, Korn R, McLaughlin J, Ohsugi M, Herrmann BG, Kemler R. Nuclear localization of beta-catenin by interaction with transcription factor LEF-1. Mech Dev 59:3–10, 1996.
Gumbiner BM. Carcinogenesis: a balance between beta-catenin and APC. Curr Biol 7:R443-R446, 1997.
Rubinfeld B, Albert I, Porfiri E, Fiol C, Munemitsu S, Polakis P. Binding of GSK3beta to the APC-beta-catenin complex and regulation of complex assembly. Science 272:1023–1026, 1996.
Sambrook J, Gisch EF, Maniatis T. A laboratory manual. 2nd ed. Isolation of high-molecular-weight DNA from mammalian cells. Cold Spring Harbor, NY, CSH Laboratory Press, 1989; 9.14–9.19.
Qian X, Jin L, Grande JP, Lloyd RV. Transforming growth factor-beta and p27 expression in pituitary cells. Endocrinology 137:3051–3060, 1996.
Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B, Kinzler KW. Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science 275:1787–1790, 1997.
Ilyas M, Tomlinson IP, Rowan A, Pignatelli M, Bodmer WF. Beta-catenin mutations in cell lines established from human colorectal cancers. Proc Natl Acad Sci USA 94:10,330–10,334, 1997.
Iwao K, Nakamori S, Kameyama M, Imaoka S, Kinoshita M, Fukui T, et al. Activation of the beta-catenin gene by interstitial deletions involving exon 3 in primary colorectal carcinomas without adenomatous polyposis coli mutations. Cancer Res 58:1021–1026, 1998.
Robbins PF, El-Gamil M, Li YF, Kawakami Y, Loftus D, Appella E, Rosenberg SA. A mutated beta-catenin gene encodes a melanoma-specific antigen recognized by tumor infiltrating lymphocytes. J Exp Med 183:1185–1192, 1996.
Rubinfeld B, Robbins P, El-Gamil M, Albert I, Porfiri E, Polakis P. Stabilization of beta-catenin by genetic defects in melanoma cell lines [see comments]. Science 275:1790–1792, 1997.
Zurawel RH, Chiappa SA, Allen C, Raffel C. Sporadic medulloblastomas contain oncogenic beta-catenin mutations. Cancer Res 58:896–899, 1998.
Miyoshi Y, Iwao K, Nagasawa Y, Aihara T, Sasaki Y, Imaoka S, et al. Activation of the beta-catenin gene in primary hepatocellular carcinomas by somatic alterations involving exon 3. Cancer Res 58:2524–2527, 1998.
de La Coste A, Romagnolo B, Billuart P, Renard CA, Buendia MA, Soubrane O, et al. Somatic mutations of the beta-catenin gene are frequent in mouse and human hepatocellular carcinomas. Proc Natl Acad Sci USA 95:8847–8851, 1998.
Palacios J, Gamallo C. Mutations in the beta-catenin gene (CTNNB1) in endometrioid ovarian carcinomas. Cancer Res 58:1344–1347, 1998.
Voeller HJ, Truica CI, Gelmann EP. Beta-catenin mutations in human prostate cancer. Cancer Res 58:2520–2523, 1998.
Caca K, Kolligs FT, Ji X, Hayes M, Qian J, Yahanda A, et al. Beta- and gamma-catenin mutations, but not E-cadherin inactivation, underlie T-cell factor/lymphoid enhancer factor transcriptional deregulation in gastric and pancreatic cancer. Cell Growth Differ 10:369–376, 1999.
Crundwell MC, Arkell DG, Gearty J, Phillips SM. Genetic alterations in incidentally diagnosed, transitional zone prostate cancer: a seven year follow-up. J Urol 158:1568–1575, 1997.
Ghadimi BM, Behrens J, Hoffmann I, Haensch W, Birchmeier W, Schlag PM. Immunohistological analysis of E-cadherin, alpha-, beta- and gamma-catenin expression in colorectal cancer: implications for cell adhesion and signaling. Eur J Cancer 35:60–65, 1999.
Mialhe A, Louis J, Montlevier S, Peoch M, Pasquier D, Bosson JL, et al. Expression of E-cadherin and alpha-, beta- and gamma-catenins in human bladder carcinomas: are they good prognostic factors? Invasion Metastasis 17:124–137, 1997.
Washington K, Chiappori A, Hamilton K, Shyr Y, Blanke C, Johnson D, et al. Expression of beta-catenin, alpha-catenin, and E-cadherin in Barrett’s esophagus and esophageal adenocarcinomas. Mod Pathol 11:805–813, 1998.
Aaltomaa S, Lipponen P, Ala-Opas M, Eskelinen M, Kosma VM. Alpha-catenin expression has prognostic value in local and locally advanced prostate cancer. Br J Cancer 80:477–482, 1999.
Davies BR, Worsley SD, Ponder BA. Expression of E-cadherin, alpha-catenin and beta-catenin in normal ovarian surface epithelium and epithelial ovarian cancers. Histopathology 32:69–80, 1998.
Gonzalez MA, Pinder SE, Wencyk PM, Bell JA, Elston CW, Nicholson RI, et al. An immunohistochemical examination of the expression of E-cadherin, alpha- and beta/gamma-catenins, and alpha2- and beta1-integrins in invasive breast cancer. J Pathol 187:523–529, 1999.
Zhang XD, Hersey P. Expression of catenins and p120cas in melanocytic nevi and cutaneous melanoma: deficient alpha-catenin expression is associated with melanoma progression. Pathology 31:239–246, 1999.
Hirvikoski P, Kumpulainen EJ, Virtaniemi JA, Helin HJ, Rantala I, Johansson RT, et al. Cytoplasmic accumulation of alpha-catenin is associated with aggressive features in laryngeal squamous-cell carcinoma. Int J Cancer 79:546–550, 1998.
Lo Muzio L, Staibano S, Pannone G, Grieco M, Mignogna MD, Cerrato A, et al. Beta- and gamma-catenin expression in oral squamous cell carcinomas. Anticancer Res 19:3817–3826, 1999.
Buchner A, Oberneder R, Riesenberg R, Keiditsch E, Hofstetter A. Expression of plakoglobin in renal cell carcinoma. Anticancer Res 18:4231–4235, 1998.
Tada H, Hatoko M, Tanaka A, Kuwahara M, Muramatsu T. Expression of desmoglein I and plakoglobin in skin carcinomas. J Cutan Pathol 27:24–29, 2000.
Valizadeh A, Karayiannakis AJ, el-Hariry I, Kmiot W, Pignatelli M. Expression of E-cadherin-associated molecules (alpha-, beta-, and gamma-catenins and p120) in colorectal polyps. Am J Pathol 150:1977–1984, 1997.
Jin L, Kulig E, Qian X, Scheitauer BW, Eberhardt NL, Lloyd RV. A human pituitary adenoma cell line proliferates and maintains some differentiated functions following expression of SV40 large T-antigen. Endocr Pathol 9:169–184, 1998.
Semba S, Kusumi R, Moriya T, Sasano H. Nuclear accumulation of beta catenin in human endocrine tumors: association with Ki-67 (MIB-1) proliferative activity. Endocr Pathol 11:243–250, 2000.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Tziortzioti, V., Ruebel, K.H., Kuroki, T. et al. Analysis of β-catenin mutations and α-, β-, and γ-catenin expression in normal and neoplastic human pituitary tissues. Endocr Pathol 12, 125–136 (2001). https://doi.org/10.1385/EP:12:2:125
Issue Date:
DOI: https://doi.org/10.1385/EP:12:2:125