Ets transcription factors play a central role in invasion and
metastasis through regulation of synthesis of
proteolytic enzymes and angiogenic molecules. The objective of this study was to investigate the role of PEA3 in
tumor progression of ovarian and
breast carcinoma metastatic to effusions, and to evaluate the expression of Ets-2 and Erg in ovarian
carcinoma. Ovarian (83 malignant effusions, 102 corresponding solid lesions) and breast (33 malignant effusions, 40 corresponding solid lesions)
carcinomas were evaluated for expression of PEA3 using
mRNA in situ Hybridization (ISH). Expression of Ets-2 and Erg
mRNA was analyzed in 50 ovarian
carcinoma effusions using the same method. PEA3
mRNA expression was comparable at all sites in ovarian
carcinoma (44 out of 83; 53% of effusions, 48 out of 102; 47% of solid
tumors). PEA3
mRNA expression in effusions correlated with
mRNA expression of the previously studied alphav (P = 0.022), alpha6 (P < 0.001) and beta1 (P < 0.001)
integrin subunits, the
matrix metalloproteinase (
MMP) inducer
EMMPRIN (P = 0.015) and
interleukin-8 (IL-8) (P = 0.033). Erg and Ets-2
mRNA was expressed in 15 out of 50 (30%) and 18 out of 50 (36%) effusions, respectively, and co-localized with PEA3 (P = 0.017 for Erg, P = 0.004 for Ets-2). In
breast carcinoma, PEA3 expression was seen in 19/40 (48%) of solid lesions, with a significant upregulation in corresponding effusions compared to primary
tumors (24 out of 33; 73%, P = 0.038). PEA3
mRNA expression in effusions obtained prior to the institution of
chemotherapy predicted significantly shorter overall survival in univariate analysis (24 vs 37 months, P = 0.03), with a similar trend for Erg (13 vs 30 months, P = 0.1). In conclusion, PEA3 is expressed at all anatomic sites in serous
ovarian cancer and co-localizes with Erg, Ets-2 and several
metastasis-associated molecules. PEA3
mRNA expression is a novel marker for
tumor progression to malignant effusion in
breast carcinoma, and predicts poor outcome in effusions sampled prior to therapeutic intervention in ovarian
carcinoma. These findings support a
biological role for
Ets transcription factors in these
malignancies and suggests that they may be targets for therapeutic intervention.