scholarly journals Serine synthesis influences tamoxifen response in ER+ human breast carcinoma

2021 ◽  
Vol 28 (1) ◽  
pp. 27-37
Author(s):  
Stephanie Metcalf ◽  
Belinda J Petri ◽  
Traci Kruer ◽  
Benjamin Green ◽  
Susan Dougherty ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Breast Carcinoma ◽  
Endocrine Resistance ◽  
Significant Proportion ◽  
Tamoxifen Resistance ◽  
Disease Recurrence ◽  
Synthetic Pathway ◽  
Phosphoserine Aminotransferase ◽  
Tamoxifen Resistant

Estrogen receptor-positive breast cancer (ER+ BC) is the most common form of breast carcinoma accounting for approximately 70% of all diagnoses. Although ER-targeted therapies have improved survival outcomes for this BC subtype, a significant proportion of patients will ultimately develop resistance to these clinical interventions, resulting in disease recurrence. Phosphoserine aminotransferase 1 (PSAT1), an enzyme within the serine synthetic pathway (SSP), has been previously implicated in endocrine resistance. Therefore, we determined whether expression of SSP enzymes, PSAT1 or phosphoglycerate dehydrogenase (PHGDH), affects the response of ER+ BC to 4-hydroxytamoxifen (4-OHT) treatment. To investigate a clinical correlation between PSAT1, PHGDH, and endocrine resistance, we examined microarray data from ER+ patients who received tamoxifen as the sole endocrine therapy. We confirmed that higher PSAT1 and PHGDH expression correlates negatively with poorer outcomes in tamoxifen-treated ER+ BC patients. Next, we found that SSP enzyme expression and serine synthesis were elevated in tamoxifen-resistant compared to tamoxifen-sensitive ER+ BC cells in vitro. To determine relevance to endocrine sensitivity, we modified the expression of either PSAT1 or PHGDH in each cell type. Overexpression of PSAT1 in tamoxifen-sensitive MCF-7 cells diminished 4-OHT inhibition on cell proliferation. Conversely, silencing of either PSAT1 or PHGDH resulted in greater sensitivity to 4-OHT treatment in LCC9 tamoxifen-resistant cells. Likewise, the combination of a PHGDH inhibitor with 4-OHT decreased LCC9 cell proliferation. Collectively, these results suggest that overexpression of serine synthetic pathway enzymes contribute to tamoxifen resistance in ER+ BC, which can be targeted as a novel combinatorial treatment option.

scholarly journals Hsa_circ_0025202 suppresses cell tumorigenesis and tamoxifen resistance via miR-197-3p/HIPK3 axis in breast cancer

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Hongjuan Li ◽  
Qing Li ◽  
Shan He
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Western Blot ◽  
Cell Cycle Progression ◽  
Tamoxifen Resistance ◽  
Potential Interaction ◽  
Circular Rnas

Abstract Background The involvement of circular RNAs (circRNAs) in tamoxifen (TAM) resistance has been identified. Herein, we aimed to identify the role and novel mechanisms of hsa_circ_0025202 in tamoxifen resistance in breast cancer (BC). Methods The levels of hsa_circ_0025202, microRNA (miR)-197-3p, and homeodomain-interacting protein kinase 3 (HIPK3) were tested using quantitative real-time polymerase chain reaction and western blot. IC50 value of TAM, cell proliferation, cell cycle, cell invasion, migration, apoptosis, western blot, and mouse xenograft assays was used to demonstrate the effects of hsa_circ_0025202, miR-197-3p, and HIPK3 on BC cell tumorigenesis and TAM resistance. Dual-luciferase report and RNA immunoprecipitation assays were applied to explore the potential interaction between miR-197-3p and hsa_circ_0025202 or HIPK3. Results Hsa_circ_0025202 was decreased in BC tissues and TAM resistant BC cells, and knockdown of hsa_circ_0025202 elevated the IC50 value of cells to TAM, led to the promotion of cell proliferation, invasion and migration, mediated cell cycle progression, and inhibited cell apoptosis in BC in vitro. Besides, the upregulation of hsa_circ_0025202 hindered tumor growth and promoted TAM sensitivity in vivo. In a mechanical study, hsa_circ_0025202 targeted miR-197-3p, and silencing of miR-197-3p reversed the regulatory effects of hsa_circ_0025202 knockdown on TAM resistance and malignant phenotypes. Additionally, HIPK3 was a target of miR-197-3p, and miR-197-3p overexpression enhanced TAM resistance and promoted cell malignant biological behaviors in BC by targeting HIPK3. Conclusion Hsa_circ_0025202 repressed cell tumorigenesis and TAM resistance via miR-197-3p/HIPK3 axis in BC, suggesting a potential therapeutic strategy to overcome chemoresistance in BC patients.

scholarly journals Thyroid Hormone and Estrogen Promote Endocrine Resistance, Proliferation, Dedifferentiation, and Cancer Stem Cells in Steroid Receptor-Positive Breast Cancers

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A982-A983
Author(s):  
Reema S Wahdan-Alaswad ◽  
Ann D Thor
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Overall Survival ◽  
Thyroid Hormone ◽  
Tumor Growth ◽  
Cross Talk ◽  
Endocrine Resistance ◽  
Oncogenic Signaling

Abstract Background: Breast cancer (BC) and thyroid disease are well-recognized comorbidities. Hyperthyroidism and supraphysiologic thyroid hormone (TH) have been shown to promote BC incidence. We recently reported that thyroid hormone replacement therapy (THRT) was significantly and independently associated with shortened disease-free and overall survival, as well as endocrine resistance only in patients with steroid receptor-positive (SR+) BC (1). TH markedly upregulated estrogen and cell cycle signaling in vivo and in vitro and promoted dedifferentiation to basaloid and pre-stem phenotypes. Metformin (Met) attenuated this shift. Mechanisms of TH-mediated endocrine therapy resistance in ER+ BC are the focus of this report. Design: Two clinical cohorts of early-stage lymph node-negative (LN-) SR+ BC patients (n=820 and n=160) were used to determine the effect of THRT on overall survival using Kaplan-Meier methods. Bi-directional cross-talk between TH and E2 was tested using different BC cell lines, ER+ PDX in vivo models, in vitro methods, and publically available in silico data for modeling. Results: Our results show that E2+TH increases cell proliferation, enhances cell cycle, and hormone-associated oncogenic signaling in SR+/ER+ BC. Given that high expression of THRA is associated with poor prognosis in SR+ BC, knockdown of THRA and ESR1 reduced cell proliferation in ER+ BC cells. ER+ PDX tumors were implanted into NSG mice containing E2 pellet and subsequently treated with TH, Tamoxifen (Tam), Fulvestrant (ICI) or Met. Our data show that TH-mediated endocrine resistance only in the E2+TH+Tam treated tumors (P<0.0001 vs E2+Tam alone). Both ICI and Met provided significant attenuation of tumor growth in vivo. RNAseq analysis of E2+TH+Tam tumors show an increase in pro-oncogenic signaling (Wnt/Fizzled, MMPs, and TCL/LEFT). Our data suggest that the use of Tam did not dampen tumor growth whereas a full ER-antagonist (ICI) or Met attenuated E2-TH mediated cross-talk and tumor growth. Conclusions: These findings suggest that TH+Tam may enhance oncogenic signaling and is associated with a significantly increase in mortality risk in ER+/SR+ BC tumors. Exogenous TH adversely affects SR+ BC and not SR- BC. Understanding the mechanism of cross-talk between TH and E2 allows us to define novel therapeutic strategies that will facilitate rapid clinical application for ER+ BC patients currently taking THRT and anti-estrogen treatments. Reference: (1) Wahdan-Alaswad et. al. Clin Cancer Res October 23 2020 DOI: 10.1158/1078-0432.CCR-20-264.

scholarly journals A data driven approach to identify ZM-447439 as a potential repurposed drug to overcome tamoxifen-resistance in breast cancer

2020 ◽  
Author(s):  
Fadhl M Alakwaa ◽  
Paula Benny ◽  
Kumardeep Chaudhary ◽  
Lana X Garmire
Keyword(s):  
Breast Cancer ◽  
Cell Culture ◽  
Scoring System ◽  
Kinase Inhibitor ◽  
Early Stage ◽  
Research Effort ◽  
Endocrine Resistance ◽  
Tamoxifen Resistance ◽  
Integrated Network

Abstract Background: Tamoxifen is the most commonly used endocrine therapy (ET) for Breast Cancer (BC) patients expressing estrogen receptors (ER), representing almost 70% of all cases. However, one third of early stage BC patients demonstrate endocrine resistance to tamoxifen over the initial five-year treatment period, prompting significant research effort on identifying other drugs to alleviate tamoxifen resistance in ER + BC patients.Methods: We combined a total of 229 tamoxifen resistant and 363 tamoxifen sensitive tumors and tumor cell lines, to select genes that showed consistency as either up- or down- regulated differential expression among these datasets. We use these genes as the input to identify the drugs and compounds in Library of Integrated Network-Based Cellular Signatures (LINCS) database that can reverse the expression of these genes. With an innovative and comprehensive scoring system, we performed quality assessment on the results and prioritized drugs. Finally, we validated top five drugs using in vitro cell culture experiments.Results: We identified that ZM-447439, an aurora kinase inhibitor, can reverse the gene signatures associated with tamoxifen resistance. This was accomplished by a novel bioinformatics approach and scoring system, screening from over 20,000 small molecules in the Library of Integrated Network-Based Cellular Signatures (LINCS) database. The in vitro cell culture experiments showed that ZM-447439 had high potency to reverse gene expression in the tamoxifen-resistance BC cell line (MCF7-RR).Conclusion: We demonstrate the utility of a bioinformatics repurposing approach to identify candidate drug ZM-447439 with the potential to treat patients with acquired tamoxifen resistance.

scholarly journals Embryonic transcription factor SOX9 drives breast cancer endocrine resistance

2017 ◽  
Vol 114 (22) ◽  
pp. E4482-E4491 ◽  
Author(s):  
Rinath Jeselsohn ◽  
MacIntosh Cornwell ◽  
Matthew Pun ◽  
Gilles Buchwalter ◽  
Mai Nguyen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Cells ◽  
Endocrine Resistance ◽  
Tamoxifen Resistance ◽  
Clinical Samples ◽  
Breast Cancers ◽  
Primary Target ◽  
Metastatic Phenotype ◽  
Clinical Observations ◽  
Tamoxifen Resistant

The estrogen receptor (ER) drives the growth of most luminal breast cancers and is the primary target of endocrine therapy. Although ER blockade with drugs such as tamoxifen is very effective, a major clinical limitation is the development of endocrine resistance especially in the setting of metastatic disease. Preclinical and clinical observations suggest that even following the development of endocrine resistance, ER signaling continues to exert a pivotal role in tumor progression in the majority of cases. Through the analysis of the ER cistrome in tamoxifen-resistant breast cancer cells, we have uncovered a role for an RUNX2–ER complex that stimulates the transcription of a set of genes, including most notably the stem cell factor SOX9, that promote proliferation and a metastatic phenotype. We show that up-regulation of SOX9 is sufficient to cause relative endocrine resistance. The gain of SOX9 as an ER-regulated gene associated with tamoxifen resistance was validated in a unique set of clinical samples supporting the need for the development of improved ER antagonists.

Amyloid precursor protein in human breast cancer An androgen‐induced gene associated with cell proliferation

2020 ◽  
Author(s):  
Lungwani Muungo
Keyword(s):  
Cell Proliferation ◽  
Prognostic Factor ◽  
Breast Carcinoma ◽  
Amyloid Precursor Protein ◽  
Precursor Protein ◽  
Type I ◽  
Proliferation Activity ◽  
Er Positive ◽  
Mcf 7

Amyloid precursor protein (APP) is a transmembrane protein thatis highly expressed in brain tissue. Recently, APP has been implicatedin some human malignancies, and its regulation by androgenshas also been demonstrated. Such findings suggest theimportance of APP in hormone-dependent breast carcinoma, butAPP has not yet been examined in breast carcinoma tissues.Therefore, in this study, we examined the biological and clinicalsignificance of APP in breast carcinoma using immunohistochemistryand in vitro studies. APP immunoreactivity was detected in57 out of 117 (49%) breast carcinoma tissues examined, and itwas positively associated with androgen receptor (AR) expression.APP immunoreactivity was also significantly associated withKi-67 LI and increased risk of recurrence in the estrogen receptor(ER)-positive cases, and was an independent prognostic factor inthese patients. Subsequent in vitro experiments demonstratedthat APP mRNA expression was significantly induced by biologicallyactive androgen dihydrotestosterone in both a dose-dependentand a time-dependent manner in MCF-7 breast carcinomacells, which was potently suppressed by an AR blocker hydroxyflutamide.Moreover, cell proliferation activity of MCF-7 andMDA-MB-231 cells was significantly associated with their APPexpression level. These findings suggest that APP is an androgeninducedgene that promotes proliferation activity of breastcarcinoma cells. Moreover, APP immunohistochemical status isconsidered a potent prognostic factor in ER-positive breast cancerpatients. (Cancer Sci 2013; 104: 1532–1538)Breast carcinoma is known as a hormone-dependent neoplasm,and estrogens play crucial roles in the developmentand ⁄ or progression of breast carcinoma. In addition, androgenreceptor (AR) is expressed in a great majority of breast carcinomatissues(1,2) and bioactive androgen dihydrotestosterone(DHT) is locally produced in the carcinoma,(3) suggesting theimportance of androgens in breast carcinoma. Androgens arein general considered to suppress breast carcinoma cell proliferation,(4,5) but some divergent findings have been reported.(6,7)Therefore, it is very important to examine molecular functionsof androgens, including exploration of the androgen-regulatedgenes, in breast carcinoma.Amyloid precursor protein (APP) is a type I transmembraneprotein, processed by a-, b- and c-secretase. One of the processedAPP products, b-amyloid, is a major component ofamyloid plaque, which is frequently detected in the brain tissueswith Alzheimer’s disease.(8) APP is also expressed in variousnonneural tissues, and it is suggested to be involved inthe growth of these cells.(9) APP has been implicated inseveral human malignancies, including lung, colon, pancreas,parathyroid, thyroid and prostate carcinomas,(10–15) and thesoluble N-terminal ectodomain fragment (sAPP) is reported tobe responsible for the pro-proliferative effects of APP on carcinomacells.(16) In addition, Takayama et al.(15) report thatAPP is an androgen-induced gene in prostate carcinoma andfunctions as an important mediator of the androgen actions.These findings suggest possible roles of APP in human breastcarcinoma associated with androgen actions and ⁄ or cell proliferation.However, details of APP have not yet been studied inbreast carcinoma, and its significance has remained largelyunclear. Therefore, in the present study, we examine APP inbreast carcinoma using immunohistochemistry and in vitrostudies

scholarly journals Oestrogen Non-Genomic Signalling is Activated in Tamoxifen-Resistant Breast Cancer

2019 ◽  
Vol 20 (11) ◽  
pp. 2773 ◽  
Author(s):  
Coralie Poulard ◽  
Julien Jacquemetton ◽  
Olivier Trédan ◽  
Pascale A. Cohen ◽  
Julie Vendrell ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Acquired Resistance ◽  
Endocrine Resistance ◽  
In Vitro Models ◽  
Proximity Ligation Assay ◽  
Breast Cancers ◽  
Cancer Management ◽  
Tamoxifen Resistant

Endocrine therapies targeting oestrogen signalling have significantly improved breast cancer management. However, their efficacy is limited by intrinsic and acquired resistance to treatment, which remains a major challenge for oestrogen receptor α (ERα)-positive tumours. Though many studies using in vitro models of endocrine resistance have identified putative actors of resistance, no consensus has been reached. We demonstrated previously that oestrogen non-genomic signalling, characterized by the formation of the ERα/Src/PI3K complex, is activated in aggressive breast cancers (BC). We wondered herein whether the activation of this pathway is also involved in resistance to endocrine therapies. We studied the interactions between ERα and Src or PI3K by proximity ligation assay (PLA) in in-vitro and in-vivo endocrine therapy-resistant breast cancer models. We reveal an increase in ERα/Src and ERα/PI3K interactions in patient-derived xenografts (PDXs) with acquired resistance to tamoxifen, as well as in tamoxifen-resistant MCF-7 cells compared to parental counterparts. Moreover, no interactions were observed in breast cancer cells resistant to other endocrine therapies. Finally, the use of a peptide inhibiting the ERα–Src interaction partially restored tamoxifen sensitivity in resistant cells, suggesting that such components could constitute promising targets to circumvent resistance to tamoxifen in BC.

scholarly journals NR4A1 Regulates Tamoxifen Resistance by Suppressing ERK Signaling in ER-Positive Breast Cancer

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1633
Author(s):  
Yu Cheon Kim ◽  
Clara Yuri Kim ◽  
Ji Hoon Oh ◽  
Myoung Hee Kim
Keyword(s):  
Breast Cancer ◽  
Tamoxifen Resistance ◽  
Erk Signaling ◽  
Tamoxifen Treatment ◽  
Loss Of Function ◽  
Mcf7 Cells ◽  
Er Positive ◽  
Tamoxifen Resistant ◽  
Positive Breast Cancer

Endocrine therapy is used to treat estrogen receptor (ER)-positive breast cancer. Tamoxifen is effective against this cancer subtype. Nonetheless, approximately 30% of patients treated with tamoxifen acquire resistance, resulting in therapeutic challenges. NR4A1 plays key roles in processes associated with carcinogenesis, apoptosis, DNA repair, proliferation, and inflammation. However, the role of NR4A1 in tamoxifen-resistant ER-positive breast cancer has not yet been elucidated. Here, we propose that NR4A1 is a promising target to overcome tamoxifen resistance. NR4A1 gene expression was downregulated in tamoxifen-resistant MCF7 (TamR) cells compared to that in MCF7 cells. Kaplan-Meier plots were used to identify high NR4A1 expression correlated with increased survival rates in patients with ER-positive breast cancer following tamoxifen treatment. Gain and loss of function experiments showed that NR4A1 restores sensitivity to tamoxifen by regulating cell proliferation, migration, invasion, and apoptosis. NR4A1 localized to the cytoplasm enhanced the expression of apoptotic factors. In silico and in vitro analyses revealed that NR4A1 enhanced responsiveness to tamoxifen by suppressing ERK signaling in ER-positive breast cancer, suggesting that the NR4A1/ERK signaling axis modulates tamoxifen resistance. These results indicate that NR4A1 could be a potential therapeutic target to overcome tamoxifen resistance in ER-positive breast cancer.

scholarly journals In Vitro Study on Apoptosis Induced by Strontium-89 in Human Breast Carcinoma Cell Line

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Cheng Wang ◽  
Jing Wang ◽  
Han Jiang ◽  
Min Zhu ◽  
Baoguo Chen ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Breast Carcinoma ◽  
Transmembrane Potential ◽  
Human Breast Carcinoma ◽  
Inhibition Rate ◽  
Human Breast ◽  
Radioactive Concentration ◽  
Mcf 7

Many radiopharmaceuticals used for medical diagnosis and therapy are beta emitters; however, the mechanism of the cell death caused by beta-irradiation is not well understood. The objective of this study was to investigate the apoptosis of human breast carcinoma MCF-7 cell lines induced by Strontium-89 (89Sr) and its regulation and control mechanism. High-metastatic Breast Carcinoma MCF-7 cells were cultured in vitro using89Sr with different radioactive concentration. The inhibition rate of cell proliferation was measured by MTT color matching method. The cell cycle retardation, apoptosis conditions, mitochondrion transmembrane potential difference and Fas expression were tested and analyzed. The genes P53 and bcl-2 expressions was also analyzed using immunity histochemical analysis. After being induced by89Sr with various of radioactive concentration, it was found that the inhibition of cell proliferation of MCF-7 cells was obviously, the retardation of cell cycle occurred mainly in G2-M. It was also found that the obvious apoptosis occurred after being induced by89Sr, the highest apoptosis rate reached 46.28%. The expressions of Fas acceptor and P53 gene increased, while bcl-2 gene expression decreasesd. These findings demonstrate that in the ranges of a certain radioactive concentration, the inhibition rate of MCF-7 cell proliferation and retardation of cell cycle had positive correlation with the concentration of89Sr. And the mitochondrion transmembrane potential decrease would induce the apoptosis of MCF-7 cell notably, which were controlled by P53 and bcl-2 genes, involved with the Fas acceptor.

scholarly journals Inhibition of O-GlcNAc transferase activates tumor-suppressor gene expression in tamoxifen-resistant breast cancer cells

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Anna Barkovskaya ◽  
Kotryna Seip ◽  
Lina Prasmickaite ◽  
Ian G. Mills ◽  
Siver A. Moestue ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Suppressor ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Tamoxifen Resistance ◽  
Breast Cancers ◽  
Number Of Patients ◽  
Tamoxifen Resistant ◽  
Glcnac Transferase

Abstract In this study, we probed the importance of O-GlcNAc transferase (OGT) activity for the survival of tamoxifen-sensitive (TamS) and tamoxifen-resistant (TamR) breast cancer cells. Tamoxifen is an antagonist of estrogen receptor (ERα), a transcription factor expressed in over 50% of breast cancers. ERα-positive breast cancers are successfully treated with tamoxifen; however, a significant number of patients develop tamoxifen-resistant disease. We show that in vitro development of tamoxifen-resistance is associated with increased sensitivity to the OGT small molecule inhibitor OSMI-1. Global transcriptome profiling revealed that TamS cells adapt to OSMI-1 treatment by increasing the expression of histone genes. This is known to mediate chromatin compaction. In contrast, TamR cells respond to OGT inhibition by activating the unfolded protein response and by significantly increasing ERRFI1 expression. ERRFI1 is an endogenous inhibitor of ERBB-signaling, which is a known driver of tamoxifen-resistance. We show that ERRFI1 is selectively downregulated in ERα-positive breast cancers and breast cancers driven by ERBB2. This likely occurs via promoter methylation. Finally, we show that increased ERRFI1 expression is associated with extended survival in patients with ERα-positive tumors (p = 9.2e−8). In summary, we show that tamoxifen-resistance is associated with sensitivity to OSMI-1, and propose that this is explained in part through an epigenetic activation of the tumor-suppressor ERRFI1 in response to OSMI-1 treatment.

scholarly journals FoxO3a as a Positive Prognostic Marker and a Therapeutic Target in Tamoxifen-Resistant Breast Cancer

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1858 ◽  
Author(s):  
Michele Pellegrino ◽  
Pietro Rizza ◽  
Ada Donà ◽  
Alessandra Nigro ◽  
Elena Ricci ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Endocrine Resistance ◽  
Breast Cancer Patients ◽  
Proteomics Data ◽  
Luminal A ◽  
Kaplan Meier ◽  
Tamoxifen Resistant

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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