Programmed Cell Death 4 inhibits breast cancer cell invasion by increasing Tissue Inhibitor of Metalloproteinases-2 expression

• Published in: Breast cancer research and treatment 2009-03, Vol.114 (2), p.203-209
• Main Authors: Nieves-Alicea, René, Colburn, Nancy H, Simeone, Ann-Marie, Tari, Ana M
• Format: Article
• Language: English
• Subjects: Apoptosis Regulatory Proteins - genetics; Biological and medical sciences; Blotting, Western; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer research; Cancer therapies; Cell death; Cellular biology; Cyclooxygenase 2 - genetics; Cyclooxygenase 2 - metabolism; Dinoprostone - metabolism; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression - physiology; Gene Expression Regulation, Neoplastic; Genes; Gynecology. Andrology. Obstetrics; Humans; Interleukin-8 - genetics; Interleukin-8 - metabolism; Mammary gland diseases; Medical sciences; Medicine; Medicine & Public Health; Neoplasm Invasiveness; Oncology; Preclinical Study; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference - drug effects; RNA, Messenger - metabolism; RNA, Small Interfering - pharmacology; RNA-Binding Proteins - genetics; Tissue Inhibitor of Metalloproteinase-2 - genetics; Tissue Inhibitor of Metalloproteinase-2 - metabolism; Tumor Cells, Cultured; Tumors
• ISSN: 0167-6806; 1573-7217
• DOI: 10.1007/s10549-008-9993-5

High levels of the cyclooxygenase-2 (COX-2) protein have been associated with invasion and metastasis of breast tumors. Both prostaglandin E₂ (PGE₂) and interleukin-8 (IL-8) have been shown to mediate the invasive activity of COX-2 in breast cancer cells. Here we expand these studies to determine how COX-2 uses PGE₂ and IL-8 to induce breast cancer cell invasion. We demonstrated that PGE₂ and IL-8 decreased the expression of the tumor suppressor protein Programmed Cell Death 4 (PDCD4). We hypothesized that suppression of PDCD4 expression is vital to the invasive activity of PGE₂ and IL-8. In MCF-7 cells overexpressing PDCD4 (MCF-7/PDCD4), PGE₂ and IL-8 failed to induce invasion, in contrast to the parental MCF-7 cells, thus indicating that PDCD4 blocks breast cancer cell invasion. MCF-7/PDCD4 cells produced higher levels of the Tissue Inhibitor of Metalloproteinases-2 (TIMP-2) than the parental cells. Silencing TIMP-2 mRNA in MCF-7/PDCD4 cells reversed the anti-invasive effects of PDCD4, allowing PGE₂ and IL-8 to induce the invasion of these cells. Here we report the novel findings that suppression of PDCD4 expression is vital for the invasive activity of COX-2 mediated by PGE₂ and IL-8, and that PDCD4 increases TIMP-2 expression to inhibit breast cancer cell invasion.