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FoxO3a as a Positive Prognostic Marker and a Therapeutic Target in Tamoxifen-Resistant Breast Cancer
Background: Resistance to endocrine treatments is a major clinical challenge in the management of estrogen receptor positive breast cancers. Although multiple mechanisms leading to endocrine resistance have been proposed, the poor outcome of this subgroup of patients demands additional studies. Meth...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966564/ https://www.ncbi.nlm.nih.gov/pubmed/31769419 http://dx.doi.org/10.3390/cancers11121858 |
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author | Pellegrino, Michele Rizza, Pietro Donà, Ada Nigro, Alessandra Ricci, Elena Fiorillo, Marco Perrotta, Ida Lanzino, Marilena Giordano, Cinzia Bonofiglio, Daniela Bruno, Rosalinda Sotgia, Federica Lisanti, Michael P. Sisci, Diego Morelli, Catia |
author_facet | Pellegrino, Michele Rizza, Pietro Donà, Ada Nigro, Alessandra Ricci, Elena Fiorillo, Marco Perrotta, Ida Lanzino, Marilena Giordano, Cinzia Bonofiglio, Daniela Bruno, Rosalinda Sotgia, Federica Lisanti, Michael P. Sisci, Diego Morelli, Catia |
author_sort | Pellegrino, Michele |
collection | PubMed |
description | Background: Resistance to endocrine treatments is a major clinical challenge in the management of estrogen receptor positive breast cancers. Although multiple mechanisms leading to endocrine resistance have been proposed, the poor outcome of this subgroup of patients demands additional studies. Methods: FoxO3a involvement in the acquisition and reversion of tamoxifen resistance was assessed in vitro in three parental ER+ breast cancer cells, MCF-7, T47D and ZR-75-1, in the deriving Tamoxifen resistant models (TamR) and in Tet-inducible TamR/FoxO3a stable cell lines, by growth curves, PLA, siRNA, RT-PCR, Western blot, Immunofluorescence, Transmission Electron Microscopy, TUNEL, cell cycle, proteomics analyses and animal models. FoxO3a clinical relevance was validated in silico by Kaplan–Meier survival curves. Results: Here, we show that tamoxifen resistant breast cancer cells (TamR) express low FoxO3a levels. The hyperactive growth factors signaling, characterizing these cells, leads to FoxO3a hyper-phosphorylation and subsequent proteasomal degradation. FoxO3a re-expression by using TamR tetracycline inducible cells or by treating TamR with the anticonvulsant lamotrigine (LTG), restored the sensitivity to the antiestrogen and strongly reduced tumor mass in TamR-derived mouse xenografts. Proteomics data unveiled novel potential mediators of FoxO3a anti-proliferative and pro-apoptotic activity, while the Kaplan–Meier analysis showed that FoxO3a is predictive of a positive response to tamoxifen therapy in Luminal A breast cancer patients. Conclusions: Altogether, our data indicate that FoxO3a is a key target to be exploited in endocrine-resistant tumors. In this context, LTG, being able to induce FoxO3a, might represent a valid candidate in combination therapy to prevent resistance to tamoxifen in patients at risk. |
format | Online Article Text |
id | pubmed-6966564 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-69665642020-01-27 FoxO3a as a Positive Prognostic Marker and a Therapeutic Target in Tamoxifen-Resistant Breast Cancer Pellegrino, Michele Rizza, Pietro Donà, Ada Nigro, Alessandra Ricci, Elena Fiorillo, Marco Perrotta, Ida Lanzino, Marilena Giordano, Cinzia Bonofiglio, Daniela Bruno, Rosalinda Sotgia, Federica Lisanti, Michael P. Sisci, Diego Morelli, Catia Cancers (Basel) Article Background: Resistance to endocrine treatments is a major clinical challenge in the management of estrogen receptor positive breast cancers. Although multiple mechanisms leading to endocrine resistance have been proposed, the poor outcome of this subgroup of patients demands additional studies. Methods: FoxO3a involvement in the acquisition and reversion of tamoxifen resistance was assessed in vitro in three parental ER+ breast cancer cells, MCF-7, T47D and ZR-75-1, in the deriving Tamoxifen resistant models (TamR) and in Tet-inducible TamR/FoxO3a stable cell lines, by growth curves, PLA, siRNA, RT-PCR, Western blot, Immunofluorescence, Transmission Electron Microscopy, TUNEL, cell cycle, proteomics analyses and animal models. FoxO3a clinical relevance was validated in silico by Kaplan–Meier survival curves. Results: Here, we show that tamoxifen resistant breast cancer cells (TamR) express low FoxO3a levels. The hyperactive growth factors signaling, characterizing these cells, leads to FoxO3a hyper-phosphorylation and subsequent proteasomal degradation. FoxO3a re-expression by using TamR tetracycline inducible cells or by treating TamR with the anticonvulsant lamotrigine (LTG), restored the sensitivity to the antiestrogen and strongly reduced tumor mass in TamR-derived mouse xenografts. Proteomics data unveiled novel potential mediators of FoxO3a anti-proliferative and pro-apoptotic activity, while the Kaplan–Meier analysis showed that FoxO3a is predictive of a positive response to tamoxifen therapy in Luminal A breast cancer patients. Conclusions: Altogether, our data indicate that FoxO3a is a key target to be exploited in endocrine-resistant tumors. In this context, LTG, being able to induce FoxO3a, might represent a valid candidate in combination therapy to prevent resistance to tamoxifen in patients at risk. MDPI 2019-11-25 /pmc/articles/PMC6966564/ /pubmed/31769419 http://dx.doi.org/10.3390/cancers11121858 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Pellegrino, Michele Rizza, Pietro Donà, Ada Nigro, Alessandra Ricci, Elena Fiorillo, Marco Perrotta, Ida Lanzino, Marilena Giordano, Cinzia Bonofiglio, Daniela Bruno, Rosalinda Sotgia, Federica Lisanti, Michael P. Sisci, Diego Morelli, Catia FoxO3a as a Positive Prognostic Marker and a Therapeutic Target in Tamoxifen-Resistant Breast Cancer |
title | FoxO3a as a Positive Prognostic Marker and a Therapeutic Target in Tamoxifen-Resistant Breast Cancer |
title_full | FoxO3a as a Positive Prognostic Marker and a Therapeutic Target in Tamoxifen-Resistant Breast Cancer |
title_fullStr | FoxO3a as a Positive Prognostic Marker and a Therapeutic Target in Tamoxifen-Resistant Breast Cancer |
title_full_unstemmed | FoxO3a as a Positive Prognostic Marker and a Therapeutic Target in Tamoxifen-Resistant Breast Cancer |
title_short | FoxO3a as a Positive Prognostic Marker and a Therapeutic Target in Tamoxifen-Resistant Breast Cancer |
title_sort | foxo3a as a positive prognostic marker and a therapeutic target in tamoxifen-resistant breast cancer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966564/ https://www.ncbi.nlm.nih.gov/pubmed/31769419 http://dx.doi.org/10.3390/cancers11121858 |
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