10779/rcsi.10786883.v1 Francesco Caiazza Francesco Caiazza Brian J. Harvey Brian J. Harvey Warren Thomas Warren Thomas Cytosolic phospholipase A2 activation correlates with HER2 overexpression and mediates estrogen-dependent breast cancer cell growth. Royal College of Surgeons in Ireland 2019 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 16:41:23 Journal contribution https://repository.rcsi.com/articles/journal_contribution/Cytosolic_phospholipase_A2_activation_correlates_with_HER2_overexpression_and_mediates_estrogen-dependent_breast_cancer_cell_growth_/10786883 <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>