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Accumulation of Nonphosphorylated ß-Catenin and c-myc in Primary and Uremic Secondary Hyperparathyroid Tumors

Department of Surgical Sciences, Endocrine Unit, Uppsala University Hospital, SE-751 85 Uppsala, Sweden

Address all correspondence and requests for reprints to: Gunnar Westin, Department of Surgical Sciences, Uppsala University Hospital, Klinisk forskningsavdelning 2, ingang 70, plan 3, lab 8, SE-751 85, Uppsala, Sweden. E-mail: gunnar.westin{at}surgsci.uu.se.

Context: Primary hyperparathyroidism (pHPT) resulting from parathyroid tumors is a common endocrine disorder with incompletely understood etiology, affecting about 1% of the adult population, with an even higher prevalence for elderly individuals. In renal failure, secondary hyperparathyroidism (sHPT) occurs with multiple tumor development as a result of calcium and vitamin D regulatory disturbance.

Objective: Aberrant Wnt/ß-catenin signaling with accumulation of ß-catenin in the cytoplasm/nucleus is involved in the development of a variety of neoplasms. The aim of this study was to evaluate whether the Wnt/ß-catenin signaling pathway is activated in parathyroid adenomas of pHPT and in hyperplastic glands from uremic patients with sHPT.

Design: Immunohistochemistry, Western blotting, real-time quantitative RT-PCR, and DNA sequencing were performed.

Results: ß-Catenin was accumulated in all analyzed parathyroid tumors (n = 47) from patients with pHPT and from patients with HPT secondary to uremia. The accumulation included nonphosphorylated, stabilized (transcriptionally active) ß-catenin. The overexpression was not related to increased ß-catenin mRNA levels. A protein-stabilizing mutation in exon 3 of ß-catenin (S37A) was detected in three of 20 pHPT tumors (15%). No mutation was detected in secondary hyperplastic glands (n = 20), and no evidence for truncated adenomatosis polyposis coli proteins was found in adenomas and secondary hyperplastic glands. Mutations in other Wnt signaling components leading to ß-catenin accumulation, other than in ß-catenin itself, are therefore anticipated. The ß-catenin target gene c-myc was overexpressed in a substantial fraction of the parathyroid tumors.

Conclusion: Our results strongly suggest that modifications in the Wnt/ß-catenin signaling pathway may be involved in the development of hyperparathyroidism.

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