FOXO3a represses VEGF expression through FOXM1-dependent and -independent mechanisms in breast cancer

Karadedou, Christina T.; Gomes, Ana; Chen, Jie; Petković, Maja; Ho, Ka-Kei; Zwolińska, Aleksandra; Feltes, A; Wong, San Yu; Chan, Kelvin Yuen-Kwong; Cheung, Yuen-Nei; Tsang, J W-H; Brosens, Jan J.; Khoo, Ui‐Soon; Lam, Eric W.‐F.

doi:10.1038/onc.2011.368

Cited by 138 publications

(144 citation statements)

References 57 publications

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“…In addition, our current study found FOXO3a, which suppresses VEGF-A expression (Karadedou, et al, 2012), experienced a subtle nuclear to cytoplasmic shift. This would predictably reduce FOXO3a nuclear activity and facilitate VEGF-A expression.…”

Section: Discussionsupporting

confidence: 48%

Effect of high-intensity exercise on aged mouse brain mitochondria, neurogenesis, and inflammation

Lezi¹,

Burns²,

Swerdlow³

2014

Neurobiology of Aging

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In aged mice we assessed how intensive exercise affects brain bioenergetics, inflammation, and neurogenesis-relevant parameters. After 8 weeks of a supra-lactate threshold treadmill exercise intervention, 21-month old C57BL/6 mice showed increased brain PGC-1α protein, mTOR and phospho-mTOR protein, citrate synthase mRNA, and mtDNA copy number. Hippocampal VEGF-A gene expression trended higher, and a positive correlation between VEGF-A and PRC mRNA levels was observed. Brain DCX, BDNF, TNF-α, and CCL11 gene expression, as well as plasma CCL11 protein levels, were unchanged. Despite these apparent negative findings, a negative correlation between plasma CCL11 protein levels and hippocampal DCX gene expression was observed; further analysis indicated exercise may mitigate this relationship. Overall, our data suggest supra-lactate threshold exercise activates a partial mitochondrial biogenesis in aged mice, and a gene (VEGF-A) known to support neurogenesis. Our data are consistent with another study that found systemic inflammation in general, and CCL11 protein specifically, suppresses hippocampal neurogenesis. Our study supports the view that intense exercise above the lactate threshold may benefit the aging brain; future studies to address the extent to which exercise-generated lactate mediates the observed effects are warranted.

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Section: Discussionsupporting

confidence: 48%

Effect of high-intensity exercise on aged mouse brain mitochondria, neurogenesis, and inflammation

Lezi¹,

Burns²,

Swerdlow³

2014

Neurobiology of Aging

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“…Indeed, our data indicate that VEGF expression are RAS -dependent in multiple systems. Furthermore, FOXO3a regulates VEGF production through FOXM1 (48). Because hypoxia increases the activity of PARPi and the combination of a PARPi and cedirainib (a VEGFR inhibitor) is highly active in patients (49), the effect of MEKi and PARPi on vascularity could contribute to activity of the combination in vivo .…”

Section: Discussionmentioning

confidence: 99%

Rational combination therapy with PARP and MEK inhibitors capitalizes on therapeutic liabilities in RAS mutant cancers

et al. 2017

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Mutant RAS has remained recalcitrant to targeted therapy efforts. Here we demonstrate that combined treatment with poly ADP ribose polymerase (PARP) inhibitors and MEK inhibitors evokes unanticipated, synergistic cytotoxic effects in vitro and in vivo in multiple RAS mutant tumor models across tumor lineages where RAS mutations are prevalent. The effects of PARP and MEK inhibitor combinations are independent of BRCA1/2 and p53 mutation status suggesting that the synergistic activity is likely to be generalizable. Synergistic activity of PARP and MEK inhibitor combinations in RAS mutant tumors is associated with: 1) induction of BIM-mediated apoptosis, 2) decrease in expression of components of the homologous recombination DNA repair pathway, 3) decrease in homologous recombination DNA damage repair capacity, 4) decrease in DNA damage checkpoint activity, 5) increase in PARP inhibitor-induced DNA damage, 6) decrease in vascularity which could increase PARP inhibitor efficacy by inducing hypoxia, and 7) elevated PARP1 protein, which increases trapping activity of PARP inhibitors. Mechanistically, enforced expression of FOXO3a, which is a target of the RAS/MAPK pathway, was sufficient to recapitulate the functional consequences of MEK inhibitors including synergy with PARP inhibitors. Thus the ability of mutant RAS to suppress FOXO3a and its reversal by MEK inhibitors accounts, at least in part, for the synergy of PARP and MEK inhibitors in RAS mutant tumors. The rational combination of PARP and MEK inhibitors warrants clinical investigation in patients with RAS mutant tumors where there are few effective therapeutic options.

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“…Previous literature have documented the tumour suppressor function of FOXO3a in breast cancer. For instance, Karadedou et al demonstrated that nuclear FOXO3a expression induced by lapatinib had a central role in the suppression of breast cancer progression and metastasis by negatively regulating VEGF expression 23. However, this study only involved the HER2-amplified breast cancer cell lines as model systems and was lacking clinical data.…”

Section: Discussionmentioning

confidence: 97%

FOXO3a expression is associated with lymph node metastasis and poor disease-free survival in triple-negative breast cancer

Rehman

Kim

et al. 2018

J Clin Pathol

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AimsForkhead box O (FOXO) transcription factors, consisting of FOXO1, FOXO3a, FOXO4 and FOXO6, are involved in carcinogenesis and tumour progression. Recent studies have suggested that FOXOs act as tumour suppressors in a variety of human cancers. This study investigated the clinicopathological significance of FOXOs in triple-negative breast cancer (TNBC).MethodsFOXO protein expressions were assessed by immunohistochemistry in 125 TNBC tissues. Correlations between FOXO protein expression and various clinicopathological parameters, including patients’ survival, were investigated. MDA-MB-468 cell line was used for in vitro cell proliferation and migration assay.ResultsFOXO1 protein expression was not observed in all 125 TNBC tissues. FOXO4 and FOXO6 protein expressions were detected in 11 (8.8%) and 14 (11.2%) TNBC tissues, respectively. Loss of FOXO4 expression was significantly associated with high histological grade (P=0.014, χ2 test), and TNBCs with positive FOXO6 expression correlated with high grade (P=0.020, χ2 test). FOXO3a expression was detected in 40 (32%) TNBC cases and correlated with adverse clinicopathological features, such as lymph node metastasis (P=0.021, χ2 test), perineural invasion (P=0.013, χ2 test) and higher Ki-67 proliferation index (P=0.048, t-test). Additionally, FOXO3a expression was significantly associated with poor disease-free survival (P=0.015, log-rank test). In the in vitro study, siRNA-mediated FOXO3a knockdown in the MDA-MB-468 cell line inhibited cell proliferation and migration.ConclusionAmong FOXO members, FOXO3a may have a potential role in promoting tumour cell migration and proliferation and may serve as a prognostic biomarker and a potential therapeutic target for TNBC.

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FOXO3a represses VEGF expression through FOXM1-dependent and -independent mechanisms in breast cancer

Cited by 138 publications

References 57 publications

Effect of high-intensity exercise on aged mouse brain mitochondria, neurogenesis, and inflammation

Effect of high-intensity exercise on aged mouse brain mitochondria, neurogenesis, and inflammation

Rational combination therapy with PARP and MEK inhibitors capitalizes on therapeutic liabilities in RAS mutant cancers

FOXO3a expression is associated with lymph node metastasis and poor disease-free survival in triple-negative breast cancer

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