Analysis of β-catenin mutations and α-, β-, and γ-catenin expression in normal and neoplastic human pituitary tissues
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.
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ABSTRACT: Deregulation of the Wnt pathway has been implicated in oncogenesis of numerous tissues including the pituitary gland. Immunohistochemical localization and quantification of β-catenin, Cyclin D1, c-MYC and Survivin expression in 47 pituitary adenomas (35 non-functioning, seven GH-secreting, three prolactinomas, two ACTH-secreting tumour) and six normal controls was undertaken in this study and correlation of protein expression to patient and tumour characteristics analysed. β-catenin was strictly membrane-bound with no difference observed between normal and tumour tissue. In contrast, Cyclin D1 and c-MYC localization was nuclear and significantly higher in tumour versus normal tissue (p < 0.05). c-MYC expression correlated negatively with age at diagnosis (p = 0.006, R = -0.395) while Cyclin D1 expression correlated positively with age (p = 0.036, R = 0.306) and was higher in males than in females (p = 0.036). c-MYC expression was significantly lower in patients with functional tumours requiring octreotide treatment and in patients with non-functioning tumours suffering from hypopituitarism. Survivin expression was extremely low in tumours and absent in normal controls. Involvement of the canonical Wnt pathway appears to be minimal, given the segregation of β-catenin to the membrane. Our data suggest that c-MYC may have an important role in early pituitary tumorigenesis while Cyclin D1 is likely to promote tumour growth at a later stage. We also report a novel gender difference in Cyclin D1 expression, the biological significance of which merits further analysis. The reported reduction of c-MYC in functional tumours subsequently treated with octreotide further supports a role of c-MYC in early tumorigenesis and not in recurrence. The decrease in c-MYC in patients with hypopituitarism provides the first in vivo evidence for hormonal regulation of c-MYC expression.Endocrine Pathology 02/2012; 23(2):123-31. DOI:10.1007/s12022-012-9197-8 · 1.64 Impact Factor
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ABSTRACT: Plakoglobin (γ-catenin) is a member of the Armadillo family of proteins and a homolog of β-catenin. As a component of both the adherens junctions and desmosomes, plakoglobin plays a pivotal role in the regulation of cell-cell adhesion. Furthermore, similar to β-catenin, plakoglobin is capable of participating in cell signaling. However, unlike β-catenin that has well-documented oncogenic potential through its involvement in the Wnt signaling pathway, plakoglobin generally acts as a tumor/metastasis suppressor. The exact roles that plakoglobin plays during tumorigenesis and metastasis are not clear; however, recent evidence suggests that it may regulate gene expression, cell proliferation, apoptosis, invasion, and migration. In this paper, we describe plakoglobin, its discovery and characterization, its role in regulating cell-cell adhesion, and its signaling capabilities in regulation of tumorigenesis and metastasis.International Journal of Cell Biology 03/2012; 2012:189521. DOI:10.1155/2012/189521
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ABSTRACT: Although pituitary tumors are mostly benign, they share certain molecular events with more malignant neoplasia, although their precise pathogenesis is far from established. The acquisition of new functional characteristics during their evolution suggests a multistep process that leads to tumor transformation. Mutations in classical tumor suppressor genes or oncogenes are infrequently associated with pituitary tumorigenesis. However, alterations in different signaling pathways, especially those involved in pituitary gland development, have emerged as significant features in pituitary adenomas. In particular, changes in inhibitory components of the β-catenin pathway and its relationship to the cadherin family of peptides may well play an important role in tumorigenesis. We review and assess the role of the β-catenin signaling pathway in the pathogenesis of pituitary adenomas.Pituitary 01/2009; 12(3):245-255. DOI:10.1007/s11102-008-0147-x · 2.22 Impact Factor