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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 …