Caiazza, Francesco Harvey, Brian J. Thomas, Warren Cytosolic phospholipase A2 activation correlates with HER2 overexpression and mediates estrogen-dependent breast cancer cell growth. <p>Cytosolic phospholipase A(2)alpha (cPLA(2)alpha) 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 E(2) release in breast cancer progression. The role of cPLA(2)alpha activation is less clear, and we recently showed that 17beta-estradiol (E2) can rapidly activate cPLA(2)alpha 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 cPLA(2)alpha enzymatic activity and overexpression of the HER2 receptor. The activation of cPLA(2)alpha 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(2)alpha phosphorylation at Ser505. There was a correlation between HER2 and cPLA(2)alpha 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 cPLA(2)alpha. Pharmacological blockade of cPLA(2)alpha 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 cPLAalpha(2) as a potential target for therapeutic intervention in endocrine-dependent and endocrine-independent breast cancer.</p> Blotting;Western;Breast Neoplasms;Cell Line;Tumor;Cell Proliferation;Estradiol;Estrogens;Gene Expression Regulation;Neoplastic;Group IV Phospholipases A2;Humans;Immunoprecipitation;Phosphorylation;Protein Binding;RNA Interference;Receptor;erbB-2;Reverse Transcriptase Polymerase Chain Reaction;Signal Transduction;Molecular Medicine 2019-11-22
    https://repository.rcsi.com/articles/journal_contribution/Cytosolic_phospholipase_A2_activation_correlates_with_HER2_overexpression_and_mediates_estrogen-dependent_breast_cancer_cell_growth_/10786883