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Mitochondrial markers predict recurrence, metastasis and tamoxifen-resistance in breast cancer patients: Early detection of treatment failure with companion diagnostics

Here, we used a data-mining and informatics approach to discover new biomarkers of resistance to hormonal therapy in breast cancer. More specifically, we investigated whether nuclear-encoded genes associated with mitochondrial biogenesis can be used to predict tumor recurrence, distant metastasis an...

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Autores principales: Sotgia, Federica, Fiorillo, Marco, Lisanti, Michael P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5620292/
https://www.ncbi.nlm.nih.gov/pubmed/28978152
http://dx.doi.org/10.18632/oncotarget.19612
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author Sotgia, Federica
Fiorillo, Marco
Lisanti, Michael P.
author_facet Sotgia, Federica
Fiorillo, Marco
Lisanti, Michael P.
author_sort Sotgia, Federica
collection PubMed
description Here, we used a data-mining and informatics approach to discover new biomarkers of resistance to hormonal therapy in breast cancer. More specifically, we investigated whether nuclear-encoded genes associated with mitochondrial biogenesis can be used to predict tumor recurrence, distant metastasis and treatment failure in high-risk breast cancer patients. Overall, this strategy allowed us to directly provide in silico validation of the prognostic value of these mitochondrial components in large and clinically relevant patient populations, with >15 years of follow-up data. For this purpose, we employed a group of 145 ER(+) luminal A breast cancer patients, with lymph-node (LN) metastasis at diagnosis, that were treated with tamoxifen, but not any chemotherapy agents. Using this approach, we identified >60 new individual mitochondrial biomarkers that predicted treatment failure and tumor recurrence, with hazard-ratios (HR) of up to 4.17 (p=2.2e-07). These include mitochondrial chaperones (HSPD1, HSPA9), membrane proteins (VDAC2, TOMM70A) and anti-oxidants (SOD2), as well as 18 different mitochondrial ribosomal proteins (MRPs) and >20 distinct components of the OXPHOS complexes. In addition, we combined 4 mitochondrial proteins (HSPD1, UQCRB, MRPL15, COX17), to generate a compact mitochondrial gene signature, associated with a HR of 5.34 (p=1e-09). This signature also successfully predicted distant metastasis and was effective in larger groups of ER(+) (N=2,447), basal (N=540) and HER2(+) (N=193) breast cancers. It was also effective in all breast cancers (N=3,180), if considered together as a single group. Based on this analysis, we conclude that mitochondrial biogenesis should be considered as a new therapeutic target for overcoming tumor recurrence, distant metastasis and treatment failure in patients with breast cancer. In summary, we identified individual mitochondrial biomarkers and 2 compact mitochondrial gene signatures that can be used to predict tamoxifen-resistance and tumor recurrence, at their initial diagnosis, in patients with advanced breast cancer. In the long-term, these mitochondrial biomarkers could provide a new companion diagnostics platform to help clinicians to accurately predict the response to hormonal therapy in ER(+) breast cancer patients, facilitating more personalized and effective treatment. Similarly, these mitochondrial markers could be used as companion diagnostics, to determine which breast cancer patients would benefit most from clinical treatments with mitochondrially-targeted anti-cancer therapeutics. Finally, we also showed that these mitochondrial markers are superior when directly compared with conventional biomarkers, such as Ki67 and PCNA.
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spelling pubmed-56202922017-10-03 Mitochondrial markers predict recurrence, metastasis and tamoxifen-resistance in breast cancer patients: Early detection of treatment failure with companion diagnostics Sotgia, Federica Fiorillo, Marco Lisanti, Michael P. Oncotarget Research Paper Here, we used a data-mining and informatics approach to discover new biomarkers of resistance to hormonal therapy in breast cancer. More specifically, we investigated whether nuclear-encoded genes associated with mitochondrial biogenesis can be used to predict tumor recurrence, distant metastasis and treatment failure in high-risk breast cancer patients. Overall, this strategy allowed us to directly provide in silico validation of the prognostic value of these mitochondrial components in large and clinically relevant patient populations, with >15 years of follow-up data. For this purpose, we employed a group of 145 ER(+) luminal A breast cancer patients, with lymph-node (LN) metastasis at diagnosis, that were treated with tamoxifen, but not any chemotherapy agents. Using this approach, we identified >60 new individual mitochondrial biomarkers that predicted treatment failure and tumor recurrence, with hazard-ratios (HR) of up to 4.17 (p=2.2e-07). These include mitochondrial chaperones (HSPD1, HSPA9), membrane proteins (VDAC2, TOMM70A) and anti-oxidants (SOD2), as well as 18 different mitochondrial ribosomal proteins (MRPs) and >20 distinct components of the OXPHOS complexes. In addition, we combined 4 mitochondrial proteins (HSPD1, UQCRB, MRPL15, COX17), to generate a compact mitochondrial gene signature, associated with a HR of 5.34 (p=1e-09). This signature also successfully predicted distant metastasis and was effective in larger groups of ER(+) (N=2,447), basal (N=540) and HER2(+) (N=193) breast cancers. It was also effective in all breast cancers (N=3,180), if considered together as a single group. Based on this analysis, we conclude that mitochondrial biogenesis should be considered as a new therapeutic target for overcoming tumor recurrence, distant metastasis and treatment failure in patients with breast cancer. In summary, we identified individual mitochondrial biomarkers and 2 compact mitochondrial gene signatures that can be used to predict tamoxifen-resistance and tumor recurrence, at their initial diagnosis, in patients with advanced breast cancer. In the long-term, these mitochondrial biomarkers could provide a new companion diagnostics platform to help clinicians to accurately predict the response to hormonal therapy in ER(+) breast cancer patients, facilitating more personalized and effective treatment. Similarly, these mitochondrial markers could be used as companion diagnostics, to determine which breast cancer patients would benefit most from clinical treatments with mitochondrially-targeted anti-cancer therapeutics. Finally, we also showed that these mitochondrial markers are superior when directly compared with conventional biomarkers, such as Ki67 and PCNA. Impact Journals LLC 2017-07-27 /pmc/articles/PMC5620292/ /pubmed/28978152 http://dx.doi.org/10.18632/oncotarget.19612 Text en Copyright: © 2017 Sotgia et al. http://creativecommons.org/licenses/by/3.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Research Paper
Sotgia, Federica
Fiorillo, Marco
Lisanti, Michael P.
Mitochondrial markers predict recurrence, metastasis and tamoxifen-resistance in breast cancer patients: Early detection of treatment failure with companion diagnostics
title Mitochondrial markers predict recurrence, metastasis and tamoxifen-resistance in breast cancer patients: Early detection of treatment failure with companion diagnostics
title_full Mitochondrial markers predict recurrence, metastasis and tamoxifen-resistance in breast cancer patients: Early detection of treatment failure with companion diagnostics
title_fullStr Mitochondrial markers predict recurrence, metastasis and tamoxifen-resistance in breast cancer patients: Early detection of treatment failure with companion diagnostics
title_full_unstemmed Mitochondrial markers predict recurrence, metastasis and tamoxifen-resistance in breast cancer patients: Early detection of treatment failure with companion diagnostics
title_short Mitochondrial markers predict recurrence, metastasis and tamoxifen-resistance in breast cancer patients: Early detection of treatment failure with companion diagnostics
title_sort mitochondrial markers predict recurrence, metastasis and tamoxifen-resistance in breast cancer patients: early detection of treatment failure with companion diagnostics
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5620292/
https://www.ncbi.nlm.nih.gov/pubmed/28978152
http://dx.doi.org/10.18632/oncotarget.19612
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