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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
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.
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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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