Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Cancer Cell International
Published in: Cancer Cell International 1/2015

Open Access 01-12-2015 | Review

Evaluating the evidence for targeting FOXO3a in breast cancer: a systematic review

Authors: Simon Taylor, Matthew Lam, Chathyan Pararasa, James EP Brown, Amtul R Carmichael, Helen R Griffiths

Published in: Cancer Cell International | Issue 1/2015

Login to get access

Abstract

Background

Tumour cells show greater dependency on glycolysis so providing a sufficient and rapid energy supply for fast growth. In many breast cancers, estrogen, progesterone and epidermal growth factor receptor-positive cells proliferate in response to growth factors and growth factor antagonists are a mainstay of treatment. However, triple negative breast cancer (TNBC) cells lack receptor expression, are frequently more aggressive and are resistant to growth factor inhibition. Downstream of growth factor receptors, signal transduction proceeds via phosphatidylinositol 3-kinase (PI3k), Akt and FOXO3a inhibition, the latter being partly responsible for coordinated increases in glycolysis and apoptosis resistance. FOXO3a may be an attractive therapeutic target for TNBC. Therefore we have undertaken a systematic review of FOXO3a as a target for breast cancer therapeutics.

Methods

Articles from NCBI were retrieved systematically when reporting primary data about FOXO3a expression in breast cancer cells after cytotoxic drug treatment.

Results

Increased FOXO3a expression is common following cytotoxic drug treatment and is associated with apoptosis and cell cycle arrest. There is some evidence that metabolic enzyme expression is also altered and that this effect is also elicited in TNBC cells. FOXO3a expression serves as a positive prognostic marker, especially in estrogen (ER) receptor positive cells.

Discussion

FOXO3a is upregulated by a number of receptor-dependent and -independent anti-cancer drugs and associates with apoptosis. The identification of microRNA that regulate FOXO3a directly suggest that it offers a tangible therapeutic target that merits wider evaluation.
Literature
1.
Andre F, Zielinski CC. Optimal strategies for the treatment of metastatic triple-negative breast cancer with currently approved agents. Ann Oncol. 2012;23 Suppl 6:vi46–51.PubMed
2.
Berrada N, Delaloge S, Andre F. Treatment of triple-negative metastatic breast cancer: toward individualized targeted treatments or chemosensitization? Ann Oncol. 2010;21 Suppl 7:vii30–5.PubMed
3.
Cleator S, Heller W, Coombes RC. Triple-negative breast cancer: therapeutic options. Lancet Oncol. 2007;8(3):235–44.CrossRefPubMed
4.
Dent R, Trudeau M, Pritchard KI, Hanna WM, Kahn HK, Sawka CA, et al. Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res. 2007;13(15 Pt 1):4429–34.CrossRefPubMed
5.
Liedtke C, Mazouni C, Hess KR, Andre F, Tordai A, Mejia JA, et al. Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol. 2008;26(8):1275–81.CrossRefPubMed
6.
Chiacchiera F, Simone C. The AMPK-FoxO3A axis as a target for cancer treatment. Cell Cycle. 2010;9(6):1091–6.CrossRefPubMed
7.
Accili D, Arden KC. FoxOs at the crossroads of cellular metabolism, differentiation, and transformation. Cell. 2004;117(4):421–6.CrossRefPubMed
8.
9.
Kroemer G, Pouyssegur J. Tumor cell metabolism: cancer’s Achilles’ heel. Cancer Cell. 2008;13(6):472–82.CrossRefPubMed
10.
Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324(5930):1029–33.CrossRefPubMedCentralPubMed
11.
Chen Z, Lu W, Garcia-Prieto C, Huang P. The Warburg effect and its cancer therapeutic implications. J Bioenerg Biomembr. 2007;39(3):267–74.CrossRefPubMed
12.
Dobson M, Ramakrishnan G, Ma S, Kaplun L, Balan V, Fridman R, et al. Bimodal regulation of FoxO3 by AKT and 14-3-3. Biochim Biophys Acta. 2011;1813(8):1453–64.CrossRefPubMedCentralPubMed
13.
Sunayama J, Tsuruta F, Masuyama N, Gotoh Y. JNK antagonizes Akt-mediated survival signals by phosphorylating 14-3-3. J Cell Biol. 2005;170(2):295–304.CrossRefPubMedCentralPubMed
14.
Gordon V, Banerji S. Molecular pathways: PI3K pathway targets in triple-negative breast cancers. Clin Cancer Res. 2013;19(14):3738–44.CrossRefPubMed
15.
Emerling BM, Weinberg F, Liu JL, Mak TW, Chandel NS. PTEN regulates p300-dependent hypoxia-inducible factor 1 transcriptional activity through Forkhead transcription factor 3a (FOXO3a). Proc Natl Acad Sci U S A. 2008;105(7):2622–7.CrossRefPubMedCentralPubMed
16.
Yang JY, Zong CS, Xia W, Yamaguchi H, Ding Q, Xie X, et al. ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation. Nat Cell Biol. 2008;10(2):138–48.CrossRefPubMedCentralPubMed
17.
Hu MC, Lee DF, Xia W, Golfman LS, Ou-Yang F, Yang JY, et al. IkappaB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a. Cell. 2004;117(2):225–37.CrossRefPubMed
18.
Sisci D, Maris P, Cesario MG, Anselmo W, Coroniti R, Trombino GE, et al. The estrogen receptor alpha is the key regulator of the bifunctional role of FoxO3a transcription factor in breast cancer motility and invasiveness. Cell Cycle. 2013;12(21):3405–20.CrossRefPubMedCentralPubMed
19.
Krol J, Francis RE, Albergaria A, Sunters A, Polychronis A, Coombes RC, et al. The transcription factor FOXO3a is a crucial cellular target of gefitinib (Iressa) in breast cancer cells. Mol Cancer Ther. 2007;6(12 Pt 1):3169–79.CrossRefPubMed
20.
Real PJ, Benito A, Cuevas J, Berciano MT, de Juan A, Coffer P, et al. Blockade of epidermal growth factor receptors chemosensitizes breast cancer cells through up-regulation of Bnip3L. Cancer Res. 2005;65(18):8151–7.CrossRefPubMed
21.
McGovern UB, Francis RE, Peck B, Guest SK, Wang J, Myatt SS, et al. Gefitinib (Iressa) represses FOXM1 expression via FOXO3a in breast cancer. Mol Cancer Ther. 2009;8(3):582–91.CrossRefPubMed
22.
Hegde PS, Rusnak D, Bertiaux M, Alligood K, Strum J, Gagnon R, et al. Delineation of molecular mechanisms of sensitivity to lapatinib in breast cancer cell lines using global gene expression profiles. Mol Cancer Ther. 2007;6(5):1629–40.CrossRefPubMed
23.
Karadedou CT, Gomes AR, Chen J, Petkovic M, Ho KK, Zwolinska AK, et al. FOXO3a represses VEGF expression through FOXM1-dependent and -independent mechanisms in breast cancer. Oncogene. 2012;31(14):1845–58.CrossRefPubMedCentralPubMed
24.
Reagan-Shaw S, Ahmad N. RNA interference-mediated depletion of phosphoinositide 3-kinase activates forkhead box class O transcription factors and induces cell cycle arrest and apoptosis in breast carcinoma cells. Cancer Res. 2006;66(2):1062–9.CrossRefPubMed
25.
Espinoza I, Liu H, Busby R, Lupu R. CCN1, a candidate target for zoledronic acid treatment in breast cancer. Mol Cancer Ther. 2011;10(5):732–41.CrossRefPubMed
26.
Delea TE, Taneja C, Sofrygin O, Kaura S, Gnant M. Cost-effectiveness of zoledronic acid plus endocrine therapy in premenopausal women with hormone-responsive early breast cancer. Clin Breast Cancer. 2010;10(4):267–74.CrossRefPubMed
27.
Brandi G, Fraternale A, Lucarini S, Paiardini M, De Santi M, Cervasi B, et al. Antitumoral activity of indole-3-carbinol cyclic tri- and tetrameric derivatives mixture in human breast cancer cells: in vitro and in vivo studies. Anticancer Agents Med Chem. 2013;13(4):654–62.CrossRefPubMed
28.
Lin C, Wu Z, Lin X, Yu C, Shi T, Zeng Y, et al. Knockdown of FLOT1 impairs cell proliferation and tumorigenicity in breast cancer through upregulation of FOXO3a. Clin Cancer Res. 2011;17(10):3089–99.CrossRefPubMed
29.
Li S, Zhou Y, Wang R, Zhang H, Dong Y, Ip C. Selenium sensitizes MCF-7 breast cancer cells to doxorubicin-induced apoptosis through modulation of phospho-Akt and its downstream substrates. Mol Cancer Ther. 2007;6(3):1031–8.CrossRefPubMed
30.
Zhao XC, Cao XC, Liu F, Quan MF, Ren KQ, Cao JG. Regulation of the FOXO3a/Bim signaling pathway by 5,7-dihydroxy-8-nitrochrysin in MDA-MB-453 breast cancer cells. Oncol Lett. 2013;5(3):929–34.PubMedCentralPubMed
31.
Xie G, Zhu X, Li Q, Gu M, He Z, Wu J, et al. SZ-685C, a marine anthraquinone, is a potent inducer of apoptosis with anticancer activity by suppression of the Akt/FOXO pathway. Br J Pharmacol. 2010;159(3):689–97.CrossRefPubMedCentralPubMed
32.
Sunters A, Madureira PA, Pomeranz KM, Aubert M, Brosens JJ, Cook SJ, et al. Paclitaxel-induced nuclear translocation of FOXO3a in breast cancer cells is mediated by c-Jun NH2-terminal kinase and Akt. Cancer Res. 2006;66(1):212–20.CrossRefPubMed
33.
Sharma G, Kar S, Palit S, Das PK. 18beta-glycyrrhetinic acid induces apoptosis through modulation of Akt/FOXO3a/Bim pathway in human breast cancer MCF-7 cells. J Cell Physiol. 2012;227(5):1923–31.CrossRefPubMed
34.
Guo S, Sonenshein GE. Forkhead box transcription factor FOXO3a regulates estrogen receptor alpha expression and is repressed by the Her-2/neu/phosphatidylinositol 3-kinase/Akt signaling pathway. Mol Cell Biol. 2004;24(19):8681–90.CrossRefPubMedCentralPubMed
35.
Kong W, He L, Coppola M, Guo J, Esposito NN, Coppola D, et al. MicroRNA-155 regulates cell survival, growth, and chemosensitivity by targeting FOXO3a in breast cancer. J Biol Chem. 2010;285(23):17869–79.CrossRefPubMedCentralPubMed
36.
Kong X, Moran MS, Zhao Y, Yang Q. Inhibition of metadherin sensitizes breast cancer cells to AZD6244. Cancer Biol Ther. 2012;13(1):43–9.CrossRefPubMed
37.
Lam M, Carmichael AR, Griffiths HR. An aqueous extract of Fagonia cretica induces DNA damage, cell cycle arrest and apoptosis in breast cancer cells via FOXO3a and p53 expression. PLoS ONE. 2012;7(6):e40152.CrossRefPubMedCentralPubMed
38.
Lin H, Dai T, Xiong H, Zhao X, Chen X, Yu C, et al. Unregulated miR-96 induces cell proliferation in human breast cancer by downregulating transcriptional factor FOXO3a. PLoS One. 2010;5(12):e15797.CrossRefPubMedCentralPubMed
39.
Liu W, Gong Y, Li H, Jiang G, Zhan S, Liu H, et al. Arsenic trioxide-induced growth arrest of breast cancer MCF-7 cells involving FOXO3a and IkappaB kinase beta expression and localization. Cancer Biother Radiopharm. 2012;27(8):504–12.CrossRefPubMedCentralPubMed
40.
Stan SD, Hahm ER, Warin R, Singh SV. Withaferin A causes FOXO3a- and Bim-dependent apoptosis and inhibits growth of human breast cancer cells in vivo. Cancer Res. 2008;68(18):7661–9.CrossRefPubMedCentralPubMed
41.
Gyurkó DM, Veres DV, Módos D, Lenti K, Korcsmáros T, Csermely P. Adaptation and learning of molecular networks as a description of cancer development at the systems-level: Potential use in anti-cancer therapies. Semin Cancer Biol. 2013;23(4):262–9.CrossRefPubMed
42.
Ferber EC, Peck B, Delpuech O, Bell GP, East P, Schulze A. FOXO3a regulates reactive oxygen metabolism by inhibiting mitochondrial gene expression. Cell Death Differ. 2012;19(6):968–79.CrossRefPubMedCentralPubMed
43.
44.
Madeira M, Mattar A, Logullo AF, Soares FA, Gebrim LH. Estrogen receptor alpha/beta ratio and estrogen receptor beta as predictors of endocrine therapy responsiveness-a randomized neoadjuvant trial comparison between anastrozole and tamoxifen for the treatment of postmenopausal breast cancer. BMC Cancer. 2013;13:425.CrossRefPubMedCentralPubMed
45.
Wong C-W, McNally C, Nickbarg E, Komm BS, Cheskis BJ. Estrogen receptor-interacting protein that modulates its nongenomic activity-crosstalk with Src/Erk phosphorylation cascade. Proc Natl Acad Sci. 2002;99(23):14783–8.CrossRefPubMedCentralPubMed
46.
Finlin BS, Gau C-L, Murphy GA, Shao H, Kimel T, Seitz RS, et al. RERG is a novel ras-related, estrogen-regulated and growth-inhibitory gene in breast cancer. J Biol Chem. 2001;276(45):42259–67.CrossRefPubMed
47.
Santo EE, Stroeken P, Sluis PV, Koster J, Versteeg R, Westerhout EM. FOXO3a is a major target of inactivation by PI3K/AKT signaling in aggressive neuroblastoma. Cancer Res. 2013;73(7):2189–98.CrossRefPubMed
48.
Yang XB, Zhao JJ, Huang CY, Wang QJ, Pan K, Wang DD, et al. Decreased expression of the FOXO3a gene is associated with poor prognosis in primary gastric adenocarcinoma patients. PLoS One. 2013;8(10):e78158.CrossRefPubMedCentralPubMed
49.
Xie C, Song LB, Wu JH, Li J, Yun JP, Lai JM, et al. Upregulator of cell proliferation predicts poor prognosis in hepatocellular carcinoma and contributes to hepatocarcinogenesis by downregulating FOXO3a. PLoS One. 2012;7(7):e40607.CrossRefPubMedCentralPubMed
50.
Ni D, Ma X, Li HZ, Gao Y, Li XT, Zhang Y, et al. Downregulation of FOXO3a promotes tumor metastasis and is associated with metastasis-free survival of patients with clear cell renal cell carcinoma. Clin Cancer Res. 2014;20(7):1779–90.CrossRefPubMed
51.
Yang JY, Chang CJ, Xia W, Wang Y, Wong KK, Engelman JA, et al. Activation of FOXO3a is sufficient to reverse mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitor chemoresistance in human cancer. Cancer Res. 2010;70(11):4709–18.CrossRefPubMedCentralPubMed
52.
Neilsen PM, Noll JE, Mattiske S, Bracken CP, Gregory PA, Schulz RB, et al. Mutant p53 drives invasion in breast tumors through up-regulation of miR-155. Oncogene. 2013;32(24):2992–3000.CrossRefPubMed
53.
Gyparaki MT, Basdra EK, Papavassiliou AG. MicroRNAs as regulatory elements in triple negative breast cancer. Cancer Lett. 2014;354(1):1–4.CrossRefPubMed
54.
Ross JS, Slodkowska EA, Symmans WF, Pusztai L, Ravdin PM, Hortobagyi GN. The HER-2 receptor and breast cancer: ten years of targeted anti-HER-2 therapy and personalized medicine. Oncologist. 2009;14(4):320–68.CrossRefPubMed
55.
Chakrabarty A, Sanchez V, Kuba MG, Rinehart C, Arteaga CL. Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors. Proc Natl Acad Sci U S A. 2012;109(8):2718–23.CrossRefPubMedCentralPubMed
56.
O’Brien NA, McDonald K, Tong L, von Euw E, Kalous O, Conklin D, et al. Targeting PI3K/mTOR overcomes resistance to HER2-targeted therapy independent of feedback activation of AKT. Clin Cancer Res. 2014;20(13):3507–20.CrossRefPubMed
Metadata
Title
Evaluating the evidence for targeting FOXO3a in breast cancer: a systematic review
Authors
Simon Taylor
Matthew Lam
Chathyan Pararasa
James EP Brown
Amtul R Carmichael
Helen R Griffiths
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2015
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-015-0156-6

Other articles of this Issue 1/2015

Cancer Cell International 1/2015 Go to the issue

Primary research

The choroid plexus may be an underestimated site of tumor invasion to the brain: an in vitro study using neuroblastoma cell lines

Primary research

Granulocyte colony-stimulating factor potentiates all-trans retinoic acid-induced granulocytic differentiation in acute promyelocytic leukemia cell line HT93A

Primary research

Celastrol induces cell cycle arrest by MicroRNA-21-mTOR-mediated inhibition p27 protein degradation in gastric cancer

Primary research

Expression of the immune regulation antigen CD70 in osteosarcoma

Primary research

Apigenin, a dietary flavonoid, inhibits proliferation of human bladder cancer T-24 cells via blocking cell cycle progression and inducing apoptosis

Primary research

MicroRNA-378-5p suppresses cell proliferation and induces apoptosis in colorectal cancer cells by targeting BRAF
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits