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

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Abstract

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.

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Acknowledgements

We thank Vanity McMurtry and Wendy Schober for their technical assistance. This work was supported in part by the Susan G. Komen Breast Cancer Foundation (to AMT) and the Cancer Center Core Grant CA16672.

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Correspondence to Ana M. Tari.

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Nieves-Alicea, R., Colburn, N.H., Simeone, AM. et al. Programmed Cell Death 4 inhibits breast cancer cell invasion by increasing Tissue Inhibitor of Metalloproteinases-2 expression. Breast Cancer Res Treat 114, 203–209 (2009). https://doi.org/10.1007/s10549-008-9993-5

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  • DOI: https://doi.org/10.1007/s10549-008-9993-5

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