The high protein expression of FOXO3, but not that of FOXO1, is associated with markers of good prognosis.
Adult
Aged
Aged, 80 and over
Apoptosis
/ genetics
Biomarkers, Tumor
/ metabolism
Breast Neoplasms
/ diagnosis
Cell Cycle
/ genetics
Cell Proliferation
/ genetics
DNA Damage
/ genetics
DNA Repair
/ genetics
Female
Forkhead Box Protein O1
/ genetics
Forkhead Box Protein O3
/ genetics
Gene Expression Regulation, Neoplastic
Humans
Kaplan-Meier Estimate
Middle Aged
Phosphatidylinositol 3-Kinases
/ metabolism
Prognosis
Proto-Oncogene Proteins c-akt
/ metabolism
RNA, Messenger
/ genetics
Signal Transduction
TOR Serine-Threonine Kinases
/ metabolism
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
24 04 2020
24 04 2020
Historique:
received:
09
08
2019
accepted:
07
04
2020
entrez:
26
4
2020
pubmed:
26
4
2020
medline:
1
12
2020
Statut:
epublish
Résumé
To better define the role of FOXO1 and FOXO3 transcriptional factors in breast carcinogenesis, we performed a comparative study of their expression at both the RNA and protein levels in a series of human breast tumors. We used qRT-PCR assay to quantify mRNA expression and Reverse Phase Protein Arrays (RPPA) to quantify protein expression in 218 breast tumors from patients with known clinical/pathological status and outcome. Weak correlations were observed between mRNA and protein expressions for both FOXO1 and FOXO3 genes. High expression of FOXO3 protein, but not FOXO1 protein, was a good prognostic marker, negatively correlated with KI67 and markers of activity of the PI3K/AKT/mTOR oncogenic pathway, and positively correlated with p53, a marker of apoptosis. Moreover, FOXO3 protein expression, but not FOXO1 protein expression, was also negatively correlated with various proteins involved in different DNA repair mechanisms. FOXO3 protein, but not FOXO1 protein, appears to be a tumor suppressor that inhibits breast cancer by altering DNA damage response (DDR), thereby inducing p53-dependent apoptosis. This antitumor effect appears to be suppressed by excessive activity of the PI3K/AKT/mTOR pathway. High FOXO3 protein expression could be a biomarker of deficient DDR in breast tumors.
Identifiants
pubmed: 32332845
doi: 10.1038/s41598-020-63895-8
pii: 10.1038/s41598-020-63895-8
pmc: PMC7181619
doi:
Substances chimiques
Biomarkers, Tumor
0
FOXO1 protein, human
0
FOXO3 protein, human
0
Forkhead Box Protein O1
0
Forkhead Box Protein O3
0
RNA, Messenger
0
MTOR protein, human
EC 2.7.1.1
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
TOR Serine-Threonine Kinases
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
6920Références
Ferlay, J. et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer 136, E359–386 (2015).
doi: 10.1002/ijc.29210
Sorlie, T. et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc. Natl. Acad. Sci. USA 100, 8418–8423 (2003).
doi: 10.1073/pnas.0932692100
Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature 490, 61–70 (2012).
doi: 10.1038/nature11412
Eijkelenboom, A. & Burgering, B. M. T. FOXOs: signalling integrators for homeostasis maintenance. Nat. Rev. Mol. Cell Biol. 14, 83–97 (2013).
doi: 10.1038/nrm3507
Bullock, M. FOXO factors and breast cancer: outfoxing endocrine resistance. Endocr. Relat. Cancer 23, R113–130 (2016).
doi: 10.1530/ERC-15-0461
Coomans de Brachène, A. & Demoulin, J.-B. FOXO transcription factors in cancer development and therapy. Cell. Mol. Life Sci. CMLS 73, 1159–1172 (2016).
doi: 10.1007/s00018-015-2112-y
Link, W. Introduction to FOXO Biology. Methods Mol. Biol. Clifton NJ 1890, 1–9 (2019).
doi: 10.1007/978-1-4939-8900-3_1
Link, W. & Fernandez-Marcos, P. J. FOXO transcription factors at the interface of metabolism and cancer. Int. J. Cancer 141, 2379–2391 (2017).
doi: 10.1002/ijc.30840
Wang, Z., Yu, T. & Huang, P. Post-translational modifications of FOXO family proteins (Review). Mol. Med. Rep. 14, 4931–4941 (2016).
doi: 10.3892/mmr.2016.5867
Brunet, A. et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96, 857–868 (1999).
doi: 10.1016/S0092-8674(00)80595-4
Jacobs, F. M. J. et al. FoxO6, a novel member of the FoxO class of transcription factors with distinct shuttling dynamics. J. Biol. Chem. 278, 35959–35967 (2003).
doi: 10.1074/jbc.M302804200
Plas, D. R. & Thompson, C. B. Akt activation promotes degradation of tuberin and FOXO3a via the proteasome. J. Biol. Chem. 278, 12361–12366 (2003).
doi: 10.1074/jbc.M213069200
Shaw, R. J. & Cantley, L. C. Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature 441, 424–430 (2006).
doi: 10.1038/nature04869
Paik, J.-H. et al. FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis. Cell 128, 309–323 (2007).
doi: 10.1016/j.cell.2006.12.029
Hu, M. C.-T. et al. IkappaB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a. Cell 117, 225–237 (2004).
doi: 10.1016/S0092-8674(04)00302-2
Zou, Y. et al. Forkhead box transcription factor FOXO3a suppresses estrogen-dependent breast cancer cell proliferation and tumorigenesis. Breast Cancer Res. BCR 10, R21 (2008).
doi: 10.1186/bcr1872
Yang, J.-Y. et al. ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation. Nat. Cell Biol. 10, 138–148 (2008).
doi: 10.1038/ncb1676
Guttilla, I. K. & White, B. A. Coordinate regulation of FOXO1 by miR-27a, miR-96, and miR-182 in breast cancer cells. J. Biol. Chem. 284, 23204–23216 (2009).
doi: 10.1074/jbc.M109.031427
Wu, Y. et al. Expression of FOXO1 is associated with GATA3 and Annexin-1 and predicts disease-free survival in breast cancer. Am. J. Cancer Res. 2, 104–115 (2012).
pubmed: 22206049
Jiang, Y., Zou, L., Lu, W.-Q., Zhang, Y. & Shen, A.-G. Foxo3a expression is a prognostic marker in breast cancer. Plos One 8, e70746 (2013).
doi: 10.1371/journal.pone.0070746
Feng, X. et al. Cdc25A regulates matrix metalloprotease 1 through Foxo1 and mediates metastasis of breast cancer cells. Mol. Cell. Biol. 31, 3457–3471 (2011).
doi: 10.1128/MCB.05523-11
Storz, P., Döppler, H., Copland, J. A., Simpson, K. J. & Toker, A. FOXO3a promotes tumor cell invasion through the induction of matrix metalloproteinases. Mol. Cell. Biol. 29, 4906–4917 (2009).
doi: 10.1128/MCB.00077-09
Rehman, A. et al. FOXO3a expression is associated with lymph node metastasis and poor disease-free survival in triple-negative breast cancer. J. Clin. Pathol., https://doi.org/10.1136/jclinpath-2018-205052 (2018).
Chen, J. et al. Constitutively nuclear FOXO3a localization predicts poor survival and promotes Akt phosphorylation in breast cancer. Plos one 5, e12293 (2010).
doi: 10.1371/journal.pone.0012293
Lallemand, F. et al. Involvement of the FOXO6 transcriptional factor in breast carcinogenesis. Oncotarget 9, 7464–7475 (2018).
doi: 10.18632/oncotarget.23779
Laplante, M. & Sabatini, D. M. mTOR signaling in growth control and disease. Cell 149, 274–293 (2012).
doi: 10.1016/j.cell.2012.03.017
Yudushkin, I. Getting the Akt Together: Guiding Intracellular Akt Activity by PI3K. Biomolecules 9, (2019).
Ciruelos Gil, E. M. Targeting the PI3K/AKT/mTOR pathway in estrogen receptor-positive breast cancer. Cancer Treat. Rev. 40, 862–871 (2014).
doi: 10.1016/j.ctrv.2014.03.004
Yu, J. S. L. & Cui, W. Proliferation, survival and metabolism: the role of PI3K/AKT/mTOR signalling in pluripotency and cell fate determination. Dev. Camb. Engl. 143, 3050–3060 (2016).
Blackford, A. N. & Jackson, S. P. ATM, ATR, and DNA-PK: The Trinity at the Heart of the DNA Damage Response. Mol. Cell 66, 801–817 (2017).
doi: 10.1016/j.molcel.2017.05.015
Nickoloff, J. A., Jones, D., Lee, S.-H., Williamson, E. A. & Hromas, R. Drugging the Cancers Addicted to DNA Repair. J. Natl. Cancer Inst. 109 (2017).
Yogosawa, S. & Yoshida, K. Tumor suppressive role for kinases phosphorylating p53 in DNA damage-induced apoptosis. Cancer Sci. 109, 3376–3382 (2018).
doi: 10.1111/cas.13792
de Sousa Abreu, R., Penalva, L. O., Marcotte, E. M. & Vogel, C. Global signatures of protein and mRNA expression levels. Mol. Biosyst. 5, 1512–1526 (2009).
pubmed: 20023718
Sisci, D. et al. The estrogen receptor α is the key regulator of the bifunctional role of FoxO3a transcription factor in breast cancer motility and invasiveness. Cell Cycle Georget. Tex 12, 3405–3420 (2013).
doi: 10.4161/cc.26421
Sunters, A. et al. FoxO3a transcriptional regulation of Bim controls apoptosis in paclitaxel-treated breast cancer cell lines. J. Biol. Chem. 278, 49795–49805 (2003).
doi: 10.1074/jbc.M309523200
Nestal de Moraes, G., Bella, L., Zona, S., Burton, M. J. & Lam, E. W.-F. Insights into a Critical Role of the FOXO3a-FOXM1 Axis in DNA Damage Response and Genotoxic Drug Resistance. Curr. Drug Targets 17, 164–177 (2016).
doi: 10.2174/1389450115666141122211549
Finak, G. et al. Gene expression signatures of morphologically normal breast tissue identify basal-like tumors. Breast Cancer Res. BCR 8, R58 (2006).
doi: 10.1186/bcr1608
Meseure, D. et al. Expression of ANRIL-Polycomb Complexes-CDKN2A/B/ARF Genes in Breast Tumors: Identification of a Two-Gene (EZH2/CBX7) Signature with Independent Prognostic Value. Mol. Cancer Res. MCR 14, 623–633 (2016).
doi: 10.1158/1541-7786.MCR-15-0418
Le Goux, C. et al. mRNA Expression levels of genes involved in antitumor immunity: Identification of a 3-gene signature associated with prognosis of muscle-invasive bladder cancer. Oncoimmunology 6, e1358330 (2017).
doi: 10.1080/2162402X.2017.1358330
Awadelkarim, K. D. et al. Quantification of PKC family genes in sporadic breast cancer by qRT-PCR: evidence that PKCι/λ overexpression is an independent prognostic factor. Int. J. Cancer 131, 2852–2862 (2012).
doi: 10.1002/ijc.27600
Rondeau, S. et al. ATM has a major role in the double-strand break repair pathway dysregulation in sporadic breast carcinomas and is an independent prognostic marker at both mRNA and protein levels. Br. J. Cancer 112, 1059–1066 (2015).
doi: 10.1038/bjc.2015.60