Endocrine Abstracts

Dopamine agonists (DAs) are usually used as first line treatment in prolactinomas. Some tumors do not normalize prolactin levels under treatment and demonstrate a more aggressive course. The mechanisms underlying this chemoresistance are poorly understood. Previous gene expression studies have focused on candidate genes such as the DA receptor 2 (DRD2) or the nerve growth factor (NGF), but transcriptome analyses comparing tumors resistant and responsive to DA are still lacking. We compared gene expression, by microarray, in lactotroph pituitary tumors from male patients either resistant to DA (n=5) or demonstrating postoperative normalization of serum prolactin levels under conventional doses of DA (n=11). A fold change (FC) of at least 1.3 with a p value <0.05 was considered significant. The expression of the top 30 deregulated genes either with the highest FC or the most significant p values was correlated to proliferation markers and tumor grade. Among candidate genes, DRD2 was in the top list of genes with the most significant differential expression (P=0.001; FC -1.3), confirming its low expression in DA resistant tumors. Moreover, we identified molecules interacting with DRD2 or implicated in its pathway: a down regulation of GPR37, a G protein-coupled receptor (GPCR), interacting with DRD2; and, using Gene Set Enrichment Analysis and Ingenuity pathway analysis, a significant loss of expression of DA uptake and of DA signaling cascade. We observed also an under expression of a cell adhesion molecule, close homolog of L1 (CHL1), coding for a protein interfering with the trafficking of the DRD2 and an overexpression of fibronectin type III domain-containing protein 1 (FNDC1), which is known to modulate the PI3K/Akt signaling pathway. Overlapping in the top 30 lists for both p value and FC, was centrosomal protein 55 (CEP55), considered as an oncogene, which was overexpressed in case of DA resistance (FC +2.5; P=0.005) and correlated positively with mitoses (r=0.63; P=0.01) and tumor grade (r=0.69; P=0.01). Interestingly, the only pathways and functions significantly activated in resistant vs DA sensitive tumors are the pathways known to induce drug resistance of cancer cells. Our findings precise the deregulation of the DRD2 pathway in resistant lactotroph tumors and show that other GPCR possibly interacting with DRD2 could be implicated. They shed light on putative new players, such as an adhesion molecule (CHL1) and an oncogene (CEP55), in the DA chemoresistance.