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

Hdl Handle:
http://hdl.handle.net/10147/127133
Title:
Cytosolic phospholipase A2 activation correlates with HER2 overexpression and mediates estrogen-dependent breast cancer cell growth.
Authors:
Caiazza, Francesco; Harvey, Brian J; Thomas, Warren
Affiliation:
Department of Molecular Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland.
Citation:
Cytosolic phospholipase A2 activation correlates with HER2 overexpression and mediates estrogen-dependent breast cancer cell growth. 2010, 24 (5):953-68 Mol. Endocrinol.
Journal:
Molecular endocrinology (Baltimore, Md.)
Issue Date:
May-2010
URI:
http://hdl.handle.net/10147/127133
DOI:
10.1210/me.2009-0293
PubMed ID:
20211985
Abstract:
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.
Item Type:
Article
Language:
en
MeSH:
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
ISSN:
1944-9917

Full metadata record

DC FieldValue Language
dc.contributor.authorCaiazza, Francescoen
dc.contributor.authorHarvey, Brian Jen
dc.contributor.authorThomas, Warrenen
dc.date.accessioned2011-04-05T10:12:03Z-
dc.date.available2011-04-05T10:12:03Z-
dc.date.issued2010-05-
dc.identifier.citationCytosolic phospholipase A2 activation correlates with HER2 overexpression and mediates estrogen-dependent breast cancer cell growth. 2010, 24 (5):953-68 Mol. Endocrinol.en
dc.identifier.issn1944-9917-
dc.identifier.pmid20211985-
dc.identifier.doi10.1210/me.2009-0293-
dc.identifier.urihttp://hdl.handle.net/10147/127133-
dc.description.abstractCytosolic 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.-
dc.language.isoenen
dc.subject.meshBlotting, Western-
dc.subject.meshBreast Neoplasms-
dc.subject.meshCell Line, Tumor-
dc.subject.meshCell Proliferation-
dc.subject.meshEstradiol-
dc.subject.meshEstrogens-
dc.subject.meshGene Expression Regulation, Neoplastic-
dc.subject.meshGroup IV Phospholipases A2-
dc.subject.meshHumans-
dc.subject.meshImmunoprecipitation-
dc.subject.meshPhosphorylation-
dc.subject.meshProtein Binding-
dc.subject.meshRNA Interference-
dc.subject.meshReceptor, erbB-2-
dc.subject.meshReverse Transcriptase Polymerase Chain Reaction-
dc.subject.meshSignal Transduction-
dc.titleCytosolic phospholipase A2 activation correlates with HER2 overexpression and mediates estrogen-dependent breast cancer cell growth.en
dc.typeArticleen
dc.contributor.departmentDepartment of Molecular Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland.en
dc.identifier.journalMolecular endocrinology (Baltimore, Md.)en
dc.description.provinceLeinster-

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