Cytosolic phospholipase A2 (cPLA2α) catalyzes the hydrolysis of membrane glycerophospholipids to release arachidonic acid, which is converted to bio-active eicosanoid lipid mediators, including prostaglandins (like PGE2) produced through cyclo-oxygenases (COX). The eicosanoid signalling contributes to cell proliferation in breast cancer, as demonstrated by numerous studies outlining a crucial role of COX-2 and PGE2 in breast carcinoma progression. The specific role of cPLA2α, however, is not established. Recent work from our group demonstrated that 17β-estradiol (E2) rapidly activated cPLA2α in MCF-7 breast carcinoma cells; leading to the hypothesis that the rapid release of bioactive lipids may play a role in the proliferative signalling responses stimulated by E2 in breast cancer. Breast carcinoma cell lines that differentially express the oestrogen receptor (ER) were used to study the molecular mechanism involved in the E2-induced rapid activation of cPLA2α, and we found that this was dependent on specific ER-mediated trans-activation of EGFR/HER2 heterodimers and downstream signalling through ERK1/2 MAPK to phosphorylate cPLA2α on Ser505. E2 also promoted cPLA2α trafficking to perinuclear membranes, and this effect was subsequent to, and dependent on, MAPK-induced phosphorylation on Ser505. The endocrine-resistant SKBR3 cell line, which over-expresses EGFR and HER2, and is ER-negative, showed elevated cPLA2α expression and activity compared to MCF-7. E2 promoted rapid activation of cPLA2α in this endocrine-resistant cell line through EGFR/HER2 trans-activation that was mediated by the G protein-coupled receptor GPR30. Inhibition of cPLA2α with a specific antagonist or by siRNA-mediated gene silencing suppressed the growth of both cell lines. cPLA2α is likely to play a key role in regulating the already established growth-promoting effects of oestrogen and COX-2 in breast cancer, balancing the cytotoxic effects of free arachidonic acid with the proliferative effects of prostaglandins.
Prague, Czech Republic
24 - 28 Apr 2010
European Society of Endocrinology