Wnt/β-catenin Signaling and Epigenetic Deregulation in Breast Cancer and Parathyroid Tumours

Sammanfattning: The Wnt/β-catenin signaling pathway is often deregulated in cancer. Here we investigate Wnt/β-catenin signaling, aberrant accumulation of β-catenin, and epigenetic deregulation in breast cancer and parathyroid tumours.An aberrantly spliced Wnt coreceptor LRP5 (LRP5Δ) is important for accumulation of nonphosphorylated active β-catenin and tumour growth in parathyroid tumours. Paper I demonstrated frequent expression of LRP5Δ in breast tumours and substantiated that breast tumour cell growth was dependent on continuous activation of the Wnt/β-catenin pathway by LRP5Δ. A LRP5 antibody reduced the levels of active β-catenin, inhibited tumour cell growth and caused apoptosis in breast cancer cells. Antibody therapy may have a significant role in the treatment of breast cancer.Paper II revealed lost expression of the tumour suppressor gene APC in parathyroid carcinomas, likely due to CpG methylation. Also accumulation of nonphosporylated active β-catenin was observed, indicating activation of Wnt/β-catenin signaling. Treatment of primary parathyroid carcinoma cells with the demethylating agent 5-aza-2’-deoxycytidine reduced the levels of active β-catenin, inhibited cell growth and caused apoptosis, suggesting that adjuvant epigenetic therapy could be considered in patients with metastatic or recurrent parathyroid carcinoma.In paper III we showed that the expression of the tumour suppressor gene HIC1 was generally reduced in parathyroid tumours of primary and secondary origin, and parathyroid carcinomas. Overexpressing HIC1 reduced cell viability and suppressed colony formation, supporting a tumour suppressor role in the parathyroid gland. Results suggested that the observed underexpression of HIC1 could be explained by epigenetic deregulation involving histone methylation rather than CpG methylation.Paper IV demonstrated increased expression of the histone methyltransferase EZH2 in parathyroid tumours of primary and secondary origin, and most apparent in parathyroid carcinomas. Decreasing EZH2 resulted in reduced cell viability and colony formation capacity suggesting that EZH2 may function as an oncogene in parathyroid tumours. Furthermore, depletion of EZH2 also reduced the amount of active β-catenin. EZH2 may represent a novel therapeutic target in parathyroid tumours.The fact that HIC1 was underexpressed and EZH2 overexpressed in parathyroid tumours regardless of the hyperparathyroid disease state may represent a possibility for a common pathway in parathyroid tumour development.