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FoxO3a as a positive prognostic marker and a therapeutic target in Tamoxifen-resistant breast cancer

Pellegrino, M; Rizza, P; Donà, A; Nigro, A; Ricci, E; Fiorillo, M; Perrotta, I; Lanzino, M; Giordano, C; Bonofiglio, D; Bruno, R; Sotgia, F; Lisanti, MP; Sisci, D; Morelli, C

FoxO3a as a positive prognostic marker and a therapeutic target in Tamoxifen-resistant breast cancer Thumbnail


Authors

M Pellegrino

P Rizza

A Donà

A Nigro

E Ricci

M Fiorillo

I Perrotta

M Lanzino

C Giordano

D Bonofiglio

R Bruno

D Sisci

C Morelli



Abstract

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.

Citation

Pellegrino, M., Rizza, P., Donà, A., Nigro, A., Ricci, E., Fiorillo, M., …Morelli, C. (2019). FoxO3a as a positive prognostic marker and a therapeutic target in Tamoxifen-resistant breast cancer. Cancers, 11(12), e1858. https://doi.org/10.3390/cancers11121858

Journal Article Type Article
Acceptance Date Nov 21, 2019
Publication Date Nov 25, 2019
Deposit Date Nov 27, 2019
Publicly Available Date Nov 27, 2019
Journal Cancers
Publisher MDPI
Volume 11
Issue 12
Pages e1858
DOI https://doi.org/10.3390/cancers11121858
Keywords breast cancer, FoxO3a, growth factors signaling, tamoxifen resistance
Publisher URL https://doi.org/10.3390/cancers11121858
Related Public URLs https://www.mdpi.com/journal/cancers
Additional Information Additional Information : ** From MDPI via Jisc Publications Router ** Licence for this article: https://creativecommons.org/licenses/by/4.0/ **Journal IDs: eissn 2072-6694 **History: published 25-11-2019; accepted 21-11-2019
Funders : Associazione Italiana per la Ricerca sul Cancro;Ministero Istruzione Università’ e Ricerca
Grant Number: IG 15738/2014