Role of cPLA2 in Endocrine-sensitive and Endocrine-resistant breast cancer cell growth

University College Dublin (2009) Proc Physiol Soc 15, PC173

Poster Communications: Role of cPLA2 in Endocrine-sensitive and Endocrine-resistant breast cancer cell growth

F. Caiazza1, W. Thomas1, B. J. Harvey1

1. Molecular Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.

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17β-estradiol (E2) is a steroid hormone that regulates many biological activities – including cell proliferation and invasiveness – in breast cancer, contributing to tumorigenesis and progression. E2 acts through its intracellular receptors (ERα and ERβ) to regulate gene transcription in the nucleus and activate rapid signaling pathways from the plasma membrane. Recent studies demonstrated a rapid, E2-induced increase in intracellular Ca2+ concentration through activation of the calcium-dependent cytosolic phospholipase A2 (cPLA2α) in the breast cancer-derived MCF-7 cell line (1). cPLA2α catalyzes the hydrolisis of membrane glycerophospholipides to release arachidonic acid (AA), which is converted to biactive eicosanoid lipid mediators (including prostaglandins produced through cycloxigenases) which can activate downstream proliferative signals (2). The rapid release of bioactive lipids may play a role in the signalling responses stimulated by E2 in breast cancer cells and contribute to proliferation, however the role of cPLA2α in breast cancer is not established. We used specific pharmacological inhibitors on model breast cancer cell lines to study the molecular mechanism of cPLA2α activation by western blotting and confocal microscopy. The E2-induced rapid activation of cPLA2α was dependent on EGFR/HER2 trans-activation, heterodimerisation 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. EGFR and/or HER2 over-expression correlates with a poor clinical outcome and resistance to endocrine therapy in breast cancer. The endocrine-resistant SKBR3 cell line over-expressed EGFR and HER2 and also showed elevated cPLA2 expression (at both the mRNA and protein level) compared to MCF-7, confirming the correlation between the eicosanoid and the EGFR signalling pathways, as suggested by other reports in the literature (3). Pharmacological blockade of cPLA2 α with a specific inhibitor impacted on cell growth in both cell lines, by reducing E2-induced proliferation and inducing apoptotis and necrosis, without affecting the invasiveness of surviving cells. cPLA2α is likely to play a key role in regulating the already established growth-promoting effects of estrogen and COX-2 in breast cancer, balancing the cytotoxic effects of free arachidonic acid with the proliferative effects of prostaglandins. Furthermore, cPLA2α could play a role in the transition of breast cancer from estrogen-dependence to estrogen-resistance through the over-activation of the EGFR signaling pathway.



Where applicable, experiments conform with Society ethical requirements.

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