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APE1 and NPM1 protect cancer cells from platinum compounds cytotoxicity and their expression pattern has a prognostic value in TNBC
BACKGROUND: Triple negative breast cancer (TNBC) is a breast cancer subgroup characterized by a lack of hormone receptors’ expression and no HER2 overexpression. These molecular features both drastically reduce treatment options and confer poor prognosis. Platinum (Pt)-salts are being investigated a...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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BioMed Central
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6631760/ https://www.ncbi.nlm.nih.gov/pubmed/31307523 http://dx.doi.org/10.1186/s13046-019-1294-9 |
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author | Malfatti, Matilde Clarissa Gerratana, Lorenzo Dalla, Emiliano Isola, Miriam Damante, Giuseppe Di Loreto, Carla Puglisi, Fabio Tell, Gianluca |
author_facet | Malfatti, Matilde Clarissa Gerratana, Lorenzo Dalla, Emiliano Isola, Miriam Damante, Giuseppe Di Loreto, Carla Puglisi, Fabio Tell, Gianluca |
author_sort | Malfatti, Matilde Clarissa |
collection | PubMed |
description | BACKGROUND: Triple negative breast cancer (TNBC) is a breast cancer subgroup characterized by a lack of hormone receptors’ expression and no HER2 overexpression. These molecular features both drastically reduce treatment options and confer poor prognosis. Platinum (Pt)-salts are being investigated as a new therapeutic strategy. The base excision repair (BER) pathway is important for resistance to Pt-based therapies. Overexpression of APE1, a pivotal enzyme of the BER pathway, as well as the expression of NPM1, a functional regulator of APE1, are associated with poor outcome and resistance to Pt-based therapies. METHODS: We evaluated the role of NPM1, APE1 and altered NPM1/APE1 interaction in the response to Pt-salts treatment in different cell lines: APE1 knockout (KO) cells, NPM1 KO cells, cell line models having an altered APE1/NPM1 interaction and HCC70 and HCC1937 TNBC cell lines, having different levels of APE1/NPM1. We evaluated the TNBC cells response to new chemotherapeutic small molecules targeting the endonuclease activity of APE1 or the APE1/NPM1 interaction, in combination with Pt-salts treatments. Expression levels’ correlation between APE1 and NPM1 and their impact on prognosis was analyzed in a cohort of TNBC patients through immunohistochemistry. Bioinformatics analysis, using TCGA datasets, was performed to predict a molecular signature of cancers based on APE1 and NPM1 expression. RESULTS: APE1 and NPM1, and their interaction as well, protect from the cytotoxicity induced by Pt-salts treatment. HCC1937 cells, having higher levels of APE1/NPM1 proteins, are more resistant to Pt-salts treatment compared to the HCC70 cells. A sensitization effect by APE1 inhibitors to Pt-compounds was observed. The association of NPM1/APE1 with cancer gene signatures highlighted alterations concerning cell-cycle dependent proteins. CONCLUSIONS: APE1 and NPM1 protect cancer cells from Pt-compounds cytotoxicity, suggesting a possible improvement of the activity of Pt-based therapy for TNBC, using the NPM1 and APE1 proteins as secondary therapeutic targets. Based on positive or negative correlation with APE1 and NPM1 gene expression levels, we finally propose several TNBC gene signatures that should deserve further attention for their potential impact on TNBC precision medicine approaches. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13046-019-1294-9) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-6631760 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-66317602019-07-24 APE1 and NPM1 protect cancer cells from platinum compounds cytotoxicity and their expression pattern has a prognostic value in TNBC Malfatti, Matilde Clarissa Gerratana, Lorenzo Dalla, Emiliano Isola, Miriam Damante, Giuseppe Di Loreto, Carla Puglisi, Fabio Tell, Gianluca J Exp Clin Cancer Res Research BACKGROUND: Triple negative breast cancer (TNBC) is a breast cancer subgroup characterized by a lack of hormone receptors’ expression and no HER2 overexpression. These molecular features both drastically reduce treatment options and confer poor prognosis. Platinum (Pt)-salts are being investigated as a new therapeutic strategy. The base excision repair (BER) pathway is important for resistance to Pt-based therapies. Overexpression of APE1, a pivotal enzyme of the BER pathway, as well as the expression of NPM1, a functional regulator of APE1, are associated with poor outcome and resistance to Pt-based therapies. METHODS: We evaluated the role of NPM1, APE1 and altered NPM1/APE1 interaction in the response to Pt-salts treatment in different cell lines: APE1 knockout (KO) cells, NPM1 KO cells, cell line models having an altered APE1/NPM1 interaction and HCC70 and HCC1937 TNBC cell lines, having different levels of APE1/NPM1. We evaluated the TNBC cells response to new chemotherapeutic small molecules targeting the endonuclease activity of APE1 or the APE1/NPM1 interaction, in combination with Pt-salts treatments. Expression levels’ correlation between APE1 and NPM1 and their impact on prognosis was analyzed in a cohort of TNBC patients through immunohistochemistry. Bioinformatics analysis, using TCGA datasets, was performed to predict a molecular signature of cancers based on APE1 and NPM1 expression. RESULTS: APE1 and NPM1, and their interaction as well, protect from the cytotoxicity induced by Pt-salts treatment. HCC1937 cells, having higher levels of APE1/NPM1 proteins, are more resistant to Pt-salts treatment compared to the HCC70 cells. A sensitization effect by APE1 inhibitors to Pt-compounds was observed. The association of NPM1/APE1 with cancer gene signatures highlighted alterations concerning cell-cycle dependent proteins. CONCLUSIONS: APE1 and NPM1 protect cancer cells from Pt-compounds cytotoxicity, suggesting a possible improvement of the activity of Pt-based therapy for TNBC, using the NPM1 and APE1 proteins as secondary therapeutic targets. Based on positive or negative correlation with APE1 and NPM1 gene expression levels, we finally propose several TNBC gene signatures that should deserve further attention for their potential impact on TNBC precision medicine approaches. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13046-019-1294-9) contains supplementary material, which is available to authorized users. BioMed Central 2019-07-15 /pmc/articles/PMC6631760/ /pubmed/31307523 http://dx.doi.org/10.1186/s13046-019-1294-9 Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Malfatti, Matilde Clarissa Gerratana, Lorenzo Dalla, Emiliano Isola, Miriam Damante, Giuseppe Di Loreto, Carla Puglisi, Fabio Tell, Gianluca APE1 and NPM1 protect cancer cells from platinum compounds cytotoxicity and their expression pattern has a prognostic value in TNBC |
title | APE1 and NPM1 protect cancer cells from platinum compounds cytotoxicity and their expression pattern has a prognostic value in TNBC |
title_full | APE1 and NPM1 protect cancer cells from platinum compounds cytotoxicity and their expression pattern has a prognostic value in TNBC |
title_fullStr | APE1 and NPM1 protect cancer cells from platinum compounds cytotoxicity and their expression pattern has a prognostic value in TNBC |
title_full_unstemmed | APE1 and NPM1 protect cancer cells from platinum compounds cytotoxicity and their expression pattern has a prognostic value in TNBC |
title_short | APE1 and NPM1 protect cancer cells from platinum compounds cytotoxicity and their expression pattern has a prognostic value in TNBC |
title_sort | ape1 and npm1 protect cancer cells from platinum compounds cytotoxicity and their expression pattern has a prognostic value in tnbc |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6631760/ https://www.ncbi.nlm.nih.gov/pubmed/31307523 http://dx.doi.org/10.1186/s13046-019-1294-9 |
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