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Secretory leukocyte protease inhibitor (SLPI) as a potential target for inhibiting metastasis of triple-negative breast cancers

SLPI has been implicated in the progression and metastasis of certain cancers. However, the effects of SLPI seem to be tumor-specific and the mechanisms remain poorly defined. Here, we demonstrate that highly metastatic, triple-negative breast cancer (TNBC) 4T1 cells secreted more SLPI compared to t...

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Autores principales: Kozin, Sergey V., Maimon, Nir, Wang, Rong, Gupta, Nisha, Munn, Lance, Jain, Rakesh K., Garkavtsev, Igor
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5752445/
https://www.ncbi.nlm.nih.gov/pubmed/29312532
http://dx.doi.org/10.18632/oncotarget.22660
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author Kozin, Sergey V.
Maimon, Nir
Wang, Rong
Gupta, Nisha
Munn, Lance
Jain, Rakesh K.
Garkavtsev, Igor
author_facet Kozin, Sergey V.
Maimon, Nir
Wang, Rong
Gupta, Nisha
Munn, Lance
Jain, Rakesh K.
Garkavtsev, Igor
author_sort Kozin, Sergey V.
collection PubMed
description SLPI has been implicated in the progression and metastasis of certain cancers. However, the effects of SLPI seem to be tumor-specific and the mechanisms remain poorly defined. Here, we demonstrate that highly metastatic, triple-negative breast cancer (TNBC) 4T1 cells secreted more SLPI compared to their non-metastatic counterparts. Furthermore, SLPI secretion directly correlated with spontaneous lung metastasis from 4T1 tumors orthotopically implanted in mice. Consistent with our experimental results, we also found that higher SLPI expression levels correlate with worse clinical outcome in basal/TNBC patients. Using high-throughput screening we identified a novel compound, C74, which significantly inhibits SLPI secretion. C74 administration in our mouse model slows the growth of primary 4T1 tumors and inhibits their dissemination to the lung. We also discovered that SLPI physically interacts with the retinoblastoma tumor suppressor protein (Rb) and releases FoxM1 from the Rb-FoxM1 complex, which may activate FoxM1 target genes involved in breast cancer metastasis.
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spelling pubmed-57524452018-01-08 Secretory leukocyte protease inhibitor (SLPI) as a potential target for inhibiting metastasis of triple-negative breast cancers Kozin, Sergey V. Maimon, Nir Wang, Rong Gupta, Nisha Munn, Lance Jain, Rakesh K. Garkavtsev, Igor Oncotarget Priority Research Paper SLPI has been implicated in the progression and metastasis of certain cancers. However, the effects of SLPI seem to be tumor-specific and the mechanisms remain poorly defined. Here, we demonstrate that highly metastatic, triple-negative breast cancer (TNBC) 4T1 cells secreted more SLPI compared to their non-metastatic counterparts. Furthermore, SLPI secretion directly correlated with spontaneous lung metastasis from 4T1 tumors orthotopically implanted in mice. Consistent with our experimental results, we also found that higher SLPI expression levels correlate with worse clinical outcome in basal/TNBC patients. Using high-throughput screening we identified a novel compound, C74, which significantly inhibits SLPI secretion. C74 administration in our mouse model slows the growth of primary 4T1 tumors and inhibits their dissemination to the lung. We also discovered that SLPI physically interacts with the retinoblastoma tumor suppressor protein (Rb) and releases FoxM1 from the Rb-FoxM1 complex, which may activate FoxM1 target genes involved in breast cancer metastasis. Impact Journals LLC 2017-11-26 /pmc/articles/PMC5752445/ /pubmed/29312532 http://dx.doi.org/10.18632/oncotarget.22660 Text en Copyright: © 2017 Kozin et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Priority Research Paper
Kozin, Sergey V.
Maimon, Nir
Wang, Rong
Gupta, Nisha
Munn, Lance
Jain, Rakesh K.
Garkavtsev, Igor
Secretory leukocyte protease inhibitor (SLPI) as a potential target for inhibiting metastasis of triple-negative breast cancers
title Secretory leukocyte protease inhibitor (SLPI) as a potential target for inhibiting metastasis of triple-negative breast cancers
title_full Secretory leukocyte protease inhibitor (SLPI) as a potential target for inhibiting metastasis of triple-negative breast cancers
title_fullStr Secretory leukocyte protease inhibitor (SLPI) as a potential target for inhibiting metastasis of triple-negative breast cancers
title_full_unstemmed Secretory leukocyte protease inhibitor (SLPI) as a potential target for inhibiting metastasis of triple-negative breast cancers
title_short Secretory leukocyte protease inhibitor (SLPI) as a potential target for inhibiting metastasis of triple-negative breast cancers
title_sort secretory leukocyte protease inhibitor (slpi) as a potential target for inhibiting metastasis of triple-negative breast cancers
topic Priority Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5752445/
https://www.ncbi.nlm.nih.gov/pubmed/29312532
http://dx.doi.org/10.18632/oncotarget.22660
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