Elevated levels of the steroidogenic factor 1 are associated with over-expression of CYP19 in an oestrogen-producing testicular Leydig cell tumour.
OBJECTIVE
Testicular Leydig cell tumours (LCTs) are rare, steroid-secreting tumours. Elevated levels of aromatase (CYP19 or CYP19A1) mRNA have been previously described in LCTs; however, little is known about the mechanism(s) causing CYP19 over-expression. We report an LCT in a 29-year-old male with elevated plasma oestradiol caused by enhanced CYP19 transcription.


METHODS
First, we measured the intra-tumour expression of CYP19 and determined the use of CYP19 promoters by qPCR. Secondly, we explored CYP19 and promoter II (PII) for gene amplifications and activating mutations in PII by sequencing. Thirdly, we analysed intra-tumour expression of steroidogenic factor 1 (SF-1 (NR5A1)), liver receptor homologue-1 (LRH-1 (NR5A2)) and cyclooxygenase-2 (COX2 (PTGS2)). Finally, we analysed SF-1 for promoter mutations and gene amplifications.


RESULTS
Similar to what has been recorded in normal Leydig cells, we first found the bulk of tumour CYP19 transcripts to be PII derived, excluding promoter shift as a cause of enhanced transcription. Secondly, we excluded CYP19 and PII gene amplifications, and activating mutations in PII, as causes of elevated CYP19 mRNA. We found SF-1 mRNA to be up-regulated in the tumour, while LRH-1 and COX2 were down-regulated. The finding of elevated SF-1 levels in the tumour was confirmed by immunohistochemistry. The elevated level of SF-1 was not due to promoter mutations or amplifications of the SF-1 gene.


CONCLUSIONS
Our results strongly suggest that the elevated levels of SF-1 have induced PII-regulated CYP19 transcription in this tumour. These findings are of relevance to the understanding of CYP19 up-regulation in general, which may occur in several tissues, including breast cancer.
Section of Oncology, Institute of Medicine, University of Bergen, Bergen, Norway.
Anne Hege
AH
Straume
Kristian
K
Løvås
Hrvoje
H
Miletic
Karsten
K
Gravdal
Per Eystein
PE
Lønning
Stian
S
Knappskog
D000328:Adult; D001141:Aromatase / Q000096:biosynthesis* / Q000235:genetics; D014408:Biomarkers, Tumor / Q000097:blood; D004967:Estrogens / Q000097:blood*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D007984:Leydig Cell Tumor / Q000097:blood* / Q000201:enzymology / Q000235:genetics; D008297:Male; D054339:Steroidogenic Factor 1 / Q000096:biosynthesis / Q000097:blood*; D013736:Testicular Neoplasms / Q000097:blood* / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics
D014408:Biomarkers, Tumor; D004967:Estrogens; C515057:NR5A1 protein, human; D054339:Steroidogenic Factor 1; D001141:Aromatase