High GATA-4 expression associates with aggressive behavior, whereas low anti-Müllerian hormone expression associates with growth potential of ovarian granulosa cell tumors.
BACKGROUND
Granulosa cell tumors (GCTs) are ovarian malignancies that produce estrogens, inhibins, and anti-Müllerian hormone (AMH). The molecular pathogenesis of GCTs is likely to involve defects in the genes regulating normal granulosa cell proliferation during folliculogenesis.


OBJECTIVE
The objective of this study was to test the role of factors regulating the normal granulosa cell function, i.e. AMH, inhibin-alpha, SF-1 (steroidogenic factor-1), and GATA transcription factors in the pathobiology and clinical behavior of GCTs.


METHODS
We selected randomly a cohort of 80 GCT patients treated at our university hospital during 1971-2003, analyzed protein expression in the tumor samples embedded on a tissue microarray by immunohistochemistry, and correlated the data to clinical and histopathological parameters.


RESULTS
We found no significant differences in the immunoreactivity levels of inhibin-alpha, GATA-6, FOG-2 (friend of GATA-2), or SF-1 in GCTs compared with normal granulosa cells. AMH expression was, however, low (i.e. reduced) in 69% of GCTs and correlated inversely with tumor size (P = 0.0025). In contrast, GATA-4 expression was high (i.e. resembled normal granulosa cells) in 44% of GCTs and correlated positively with clinical stage and recurrence (P = 0.0232 and P = 0.0038, respectively). Fifty of the 80 patients had a follow-up for at least 10 yr, and 13 of them had recurrence(s). In multivariate analysis of recurrence, the high GATA-4 expression remained the only independent factor (risk ratio, 9.2; 95% confidence interval, 2.0-43.3; P = 0.0048).


CONCLUSIONS
The more aggressive GCTs retain a high GATA-4 expression, whereas the larger tumors lose the proliferation-suppressing AMH expression. The high GATA-4 expression in GCTs may serve as a marker of poor prognosis.
Anttonen
Mikko
M
Program for Developmental and Reproductive Biology, Biomedicum Helsinki, University of Helsinki, P.O. Box 63 (Haartmaninkatu 8), 00014 Helsinki, Finland. mikko.anttonen@helsinki.fi
Unkila-Kallio
Leila
L
Leminen
Arto
A
Butzow
Ralf
R
Heikinheimo
Markku
M
D000328:Adult; D000368:Aged; D054304:Anti-Mullerian Hormone; D015331:Cohort Studies; D005260:Female; D050991:GATA4 Transcription Factor / Q000378:metabolism*; D050993:GATA6 Transcription Factor / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism*; D006106:Granulosa Cell Tumor / Q000378:metabolism* / Q000473:pathology*; D006107:Granulosa Cells / Q000378:metabolism; D006801:Humans; D008875:Middle Aged; D008940:Mitotic Index; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology*; D012307:Risk Factors; D054339:Steroidogenic Factor 1; D013735:Testicular Hormones / Q000378:metabolism*
D050991:GATA4 Transcription Factor; D050993:GATA6 Transcription Factor; D006023:Glycoproteins; C515057:NR5A1 protein, human; D054339:Steroidogenic Factor 1; D013735:Testicular Hormones; D054304:Anti-Mullerian Hormone