Expression of genes in the PI3K/Akt pathway in canine cortisol-secreting adrenocortical tumors

Abstract

Conventional surgical and medical treatment of canine cortisol-secreting adrenocortical tumors is associated with a high risk of complications and negative side effects. The need for novel, more effective treatment options is increasing. The development of ‘Targeted drugs’ might provide new treatment options. The PI3K/Akt/mTOR signaling pathway have been studied in the last years in order to find more effective cancer therapies. In human tumors, dysregulation of multiple components of this pathway has been observed frequently in adrenocortical tumors. Therefore, it is an interesting pathway in canine cortisol-secreting adrenocortical tumors. In this study, the mRNA expression of ErbB1, ErbB2, ErbB3,ErbB4, ID1, ID2, Snail, Slug, Cyclin D1, PTEN, BCL2 and COX 2 was investigated in 20 canine adrenocortical carcinomas, 10 adenomas, and 10 healthy adrenal glands. All tumors were cortisol secreting. These 12 target genes and also 14 reference genes were quantified by means of a quantitative RT-polymerase chain reaction (qPCR). Mann Whitney U tests revealed that there was a significant up-regulation of ErbB2 and Snail in the group of carcinomas, compared to the normal adrenal tissue. The carcinomas showed a significant down-regulation of ErbB3 and ErbB4 in comparison with normal adrenals. The adenomas showed a significant down-regulation of ErbB4 and Cyclin D1. ErbB2 was significantly up-regulated in the carcinomas compared to the adenomas. In samples with a fold change of 0,1 or lower for ErbB2, mutation analysis was performed on exon 15 of bRAF, as mutations in this gene are known to result in a down-regulation of ErbB2. There were no amino-acid chaning mutations found in exon 15 of bRAF in this study, so this cannot be an explanation of the low ErbB3 expression in the sequenced samples. The expression of the genes did not represent an obvious activation of the PI3K/Akt/mTOR pathway.