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PED Mediates AKT-Dependent Chemoresistance in Human Breast Cancer Cells

Departments of ¹ Cellular and Molecular Biology and Pathology and ² Endocrinology and Molecular and Clinical Oncology, "Federico II" University of Naples, Naples; ³ Department of Surgical and Oncological Sciences, ⁴ Pathology Institute, University of Palermo, Palermo; ⁵ Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, and Instituto Oncologico del Mediterraneo, Catania, Italy

Requests for reprints: Gerolama Condorelli, Dipartimento di Biologia e Patologia Cellulare e Molecolare, Facoltà di Scienze Biotecnologiche, Università degli Studi di Napoli "Federico II", Via Pansini 5, 80131 Naples, Italy. Phone: 39-81-746-2768; Fax: 39-81-770-1016; E-mail: gecondor{at}unina.it.

Killing of tumor cells by cytotoxic therapies, such as chemotherapy or gamma-irradiation, is predominantly mediated by the activation of apoptotic pathways. Refractoriness to anticancer therapy is often due to a failure in the apoptotic pathway. The mechanisms that control the balance between survival and cell death in cancer cells are still largely unknown. Tumor cells have been shown to evade death signals through an increase in the expression of antiapoptotic molecules or loss of proapoptotic factors. We aimed to study the involvement of PED, a molecule with a broad antiapoptotic action, in human breast cancer cell resistance to chemotherapeutic drugs–induced cell death. We show that human breast cancer cells express high levels of PED and that AKT activity regulates PED protein levels. Interestingly, exogenous expression of a dominant-negative AKT cDNA or of PED antisense in human breast cancer cells induced a significant down-regulation of PED and sensitized cells to chemotherapy-induced cell death. Thus, AKT-dependent increase of PED expression levels represents a key molecular mechanism for chemoresistance in breast cancer.

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