Cytosolic phospholipase A2 activation correlates with HER2 overexpression and mediates estrogen-dependent breast cancer cell growth

Abstract

Cytosolic phospholipase A2α(cPLA2α) catalyzes the hydrolysis of membrane glycerol-phospholipids to release arachidonic acid as the first step of the eicosanoid signaling pathway. This pathway contributes to proliferation in breast cancer, and numerous studies have demonstrated a crucial role of cyclooxygenase 2 and prostaglandin E2 release in breast cancer progression. The role of cPLA2α activation is less clear, and we recently showed that 17β-estradiol (E2) can rapidly activate cPLA2α in MCF-7 breast cancer cells. Overexpression or gene amplification of HER2 is found in approximately 30% of breast cancer patients and correlates with a poor clinical outcome and resistance to endocrine therapy. This study reports the first evidence for a correlation between cPLA2α enzymatic activity and overexpression of the HER2 receptor. The activation of cPLA2α in response to E2 treatment was biphasic with the first phase dependent on trans-activation through the matrix metalloproteinase-dependent release of heparin-bound epidermal growth factor. EGFR/HER2 heterodimerization resulted in downstream signaling through the ERK1/2 cascade to promote cPLA 2α phosphorylation at Ser505. There was a correlation between HER2 and cPLA2α expression in six breast cancer cell lines examined, and inhibition of HER2 activation or expression in the SKBR3 cell line using herceptin or HER2-specific small interfering RNA, respectively, resulted in decreased activation and expression of cPLA2α. Pharmacological blockade of cPLA2α using a specific antagonist suppressed the growth of both MCF-7 and SKBR3 cells by reducing E2-induced proliferation and by stimulating cellular apoptosis and necrosis. This study highlights cPLAα2 as a potential target for therapeutic intervention in endocrine-dependent and endocrine-independent breast cancer. Copyright © 2010 by The Endocrine Society.