Gene Expression Alterations in Endocrine Tumors

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(1) Expression of cell cycle-related genes in parathyroid tumors with MEN1 gene mutations
The MEN1 gene function is lost by the inactivation of both MEN1 alleles not only in the endocrine tumors associated with the familial cancer syndrome multiple endocrine neoplasia type 1 (MEN1) but also in a subset of non-hereditary endocrine tumors. Loss of menin has been reported to be associated with lowered caspase 8 expression and resistance to apoptosis in murine fibroblasts and in pancreatic islet tumors arising in the animal model of the MEN1 syndrome. We examined the expression of menin, caspase 8 and cyclin-dependent kinase inhibitors in human parathyroid tumors from patients with MEN1 and those with non-hereditary primary hyperparathyroidism . The menin and p27Kip1 expression levels were correlated with MEN1 mutation status. The caspase 8 and p15Ink4b protein levels were variable among tumors, and were not correlated with menin protein levels. These findings suggest that human endocrine tumors lacking menin may not always exhibit lowered caspase 8 expression and hence may not be resistant to apoptosis-inducing therapy.

(2) Dopamine receptor expression and response to dopamine agonists in prolactinoma
The first line treatment of prolactinoma is administration of dopamine (DA) agonists, which normalize plasma prolactin levels and reduce the tumor size of DA-sensitive prolactinomas. Ten to 15 per cent of prolactinoma cases are resistant to DA agonists from the beginning of the treatment (primary resistance) and are treated with a surgical operation. A few prolactinomas initially respond to DA agonists but become resistant after prolonged treatment (secondary resistance). Although reduced dopamine D2 receptor (D2R) expression in tumor cells may explain the refractory response to DA agonists, the exact mechanism of resistance is not well understood. We analyzed surgically resected prolactinomas, which were divided into three groups according to the responsiveness to DA agonists, the dopamine-sensitive, the primary resistant and the secondary resistant tumors. Total D2R mRNA and the ratio of mRNAs for D2R short and D2R long isoforms were measured by quantitative PCR. The D2R expression was much lower in the secondary resistant tumors than in others. The D2R expression in primary resistant tumors was also significantly lower than that in sensitive tumors. The D2R short/ D2R long isoform mRNA ratio was not correlated with tumor response to DA agonists. Thus, the resistance of prolactinoma to DA agonists was correlated with the reduction of total D2R mRNA levels, suggesting that the reduced D2R gene expression is a mechanism for DA resistance of prolactinoma.