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

BackgroundTumour 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.MethodsArticles from NCBI were retrieved systematically when reporting primary data about FOXO3a expression in breast cancer cells after cytotoxic drug treatment.ResultsIncreased 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.DiscussionFOXO3a 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.

[1]  H. Griffiths,et al.  An Aqueous Extract of Fagonia cretica Induces DNA Damage, Cell Cycle Arrest and Apoptosis in Breast Cancer Cells via FOXO3a and p53 Expression , 2012, PloS one.

[2]  J. Yun,et al.  Upregulator of Cell Proliferation Predicts Poor Prognosis in Hepatocellular Carcinoma and Contributes to Hepatocarcinogenesis by Downregulating FOXO3a , 2012, PloS one.

[3]  A. Papavassiliou,et al.  MicroRNAs as regulatory elements in triple negative breast cancer. , 2014, Cancer letters.

[4]  R. Lupu,et al.  CCN1, a Candidate Target for Zoledronic Acid Treatment in Breast Cancer , 2011, Molecular Cancer Therapeutics.

[5]  Ying Jiang,et al.  Foxo3a Expression Is a Prognostic Marker in Breast Cancer , 2013, PloS one.

[6]  Carlos L. Arteaga,et al.  Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors , 2011, Proceedings of the National Academy of Sciences.

[7]  Jan Koster,et al.  FOXO3a is a major target of inactivation by PI3K/AKT signaling in aggressive neuroblastoma. , 2013, Cancer research.

[8]  N. Ahmad,et al.  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. , 2006, Cancer research.

[9]  G. Hortobagyi,et al.  Activation of FOXO3a is sufficient to reverse mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitor chemoresistance in human cancer. , 2010, Cancer research.

[10]  Jueheng Wu,et al.  SZ‐685C, a marine anthraquinone, is a potent inducer of apoptosis with anticancer activity by suppression of the Akt/FOXO pathway , 2010, British journal of pharmacology.

[11]  Guido Kroemer,et al.  Tumor cell metabolism: cancer's Achilles' heel. , 2008, Cancer cell.

[12]  Ryuji Kobayashi,et al.  IκB Kinase Promotes Tumorigenesis through Inhibition of Forkhead FOXO3a , 2004, Cell.

[13]  O. Delpuech,et al.  FOXO3a regulates reactive oxygen metabolism by inhibiting mitochondrial gene expression , 2011, Cell Death and Differentiation.

[14]  C. Simone,et al.  The AMPK-FoxO3A axis as a target for cancer treatment , 2010, Cell cycle.

[15]  P. Real,et al.  Blockade of epidermal growth factor receptors chemosensitizes breast cancer cells through up-regulation of Bnip3L. , 2005, Cancer research.

[16]  David Botstein,et al.  RERG Is a Novel ras-related, Estrogen-regulated and Growth-inhibitory Gene in Breast Cancer* , 2001, The Journal of Biological Chemistry.

[17]  Chi-Wai Wong,et al.  Estrogen receptor-interacting protein that modulates its nongenomic activity-crosstalk with Src/Erk phosphorylation cascade , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[18]  C. Schnell,et al.  Targeting PI3K/mTOR Overcomes Resistance to HER2-Targeted Therapy Independent of Feedback Activation of AKT , 2014, Clinical Cancer Research.

[19]  Libing Song,et al.  Knockdown of FLOT1 Impairs Cell Proliferation and Tumorigenicity in Breast Cancer through Upregulation of FOXO3a , 2011, Clinical Cancer Research.

[20]  J. Ross,et al.  The HER-2 receptor and breast cancer: ten years of targeted anti-HER-2 therapy and personalized medicine. , 2009, The oncologist.

[21]  E. Lam,et al.  The transcription factor FOXO3a is a crucial cellular target of gefitinib (Iressa) in breast cancer cells , 2007, Molecular Cancer Therapeutics.

[22]  Xiaobo Yang,et al.  Decreased Expression of the FOXO3a Gene Is Associated with Poor Prognosis in Primary Gastric Adenocarcinoma Patients , 2013, PloS one.

[23]  C. Bracken,et al.  Mutant p53 drives invasion in breast tumors through up-regulation of miR-155 , 2013, Oncogene.

[24]  Hong-zhao Li,et al.  Downregulation of FOXO3a Promotes Tumor Metastasis and Is Associated with Metastasis-Free Survival of Patients with Clear Cell Renal Cell Carcinoma , 2014, Clinical Cancer Research.

[25]  T. Mak,et al.  PTEN regulates p300-dependent hypoxia-inducible factor 1 transcriptional activity through Forkhead transcription factor 3a (FOXO3a) , 2008, Proceedings of the National Academy of Sciences.

[26]  W. Kong,et al.  MicroRNA-155 regulates cell survival, growth, and chemosensitivity by targeting FOXO3a in breast cancer. , 2016, The Journal of Biological Chemistry.

[27]  F. André,et al.  Optimal strategies for the treatment of metastatic triple-negative breast cancer with currently approved agents. , 2012, Annals of oncology : official journal of the European Society for Medical Oncology.

[28]  Shivendra V. Singh,et al.  Withaferin A causes FOXO3a- and Bim-dependent apoptosis and inhibits growth of human breast cancer cells in vivo. , 2008, Cancer research.

[29]  Fei Liu,et al.  Regulation of the FOXO3a/Bim signaling pathway by 5,7-dihydroxy-8-nitrochrysin in MDA-MB-453 breast cancer cells , 2012, Oncology letters.

[30]  F. André,et al.  Treatment of triple-negative metastatic breast cancer: toward individualized targeted treatments or chemosensitization? , 2010, Annals of oncology : official journal of the European Society for Medical Oncology.

[31]  Wolfgang Heller,et al.  Triple-negative breast cancer: therapeutic options. , 2007, The Lancet. Oncology.

[32]  T. Delea,et al.  Cost-effectiveness of zoledronic acid plus endocrine therapy in premenopausal women with hormone-responsive early breast cancer. , 2010, Clinical breast cancer.

[33]  Hong Liu,et al.  Arsenic trioxide-induced growth arrest of breast cancer MCF-7 cells involving FOXO3a and IκB kinase β expression and localization. , 2012, Cancer biotherapy & radiopharmaceuticals.

[34]  Libing Song,et al.  Unregulated miR-96 Induces Cell Proliferation in Human Breast Cancer by Downregulating Transcriptional Factor FOXO3a , 2010, PloS one.

[35]  Shantanu Banerji,et al.  Molecular Pathways Molecular Pathways : PI 3 K Pathway Targets in Triple-Negative Breast Cancers , 2013 .

[36]  E. Lam,et al.  FOXO3a represses VEGF expression through FOXM1-dependent and -independent mechanisms in breast cancer , 2011, Oncogene.

[37]  Tamás Korcsmáros,et al.  Adaptation and learning of molecular networks as a description of cancer development at the systems-level: potential use in anti-cancer therapies. , 2013, Seminars in cancer biology.

[38]  D. Accili,et al.  FoxOs at the Crossroads of Cellular Metabolism, Differentiation, and Transformation , 2004, Cell.

[39]  K. Hess,et al.  Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[40]  Fuminori Tsuruta,et al.  JNK antagonizes Akt-mediated survival signals by phosphorylating 14-3-3 , 2005, The Journal of cell biology.

[41]  Qifeng Yang,et al.  Inhibition of metadherin sensitizes breast cancer cells to AZD6244 , 2012, Cancer biology & therapy.

[42]  G. Tzivion,et al.  Bimodal regulation of FoxO3 by AKT and 14-3-3. , 2011, Biochimica et biophysica acta.

[43]  A. Duranti,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. , 2013, Anti-cancer agents in medicinal chemistry.

[44]  P. Hegde,et al.  Delineation of molecular mechanisms of sensitivity to lapatinib in breast cancer cell lines using global gene expression profiles , 2007, Molecular Cancer Therapeutics.

[45]  Ryuji Kobayashi,et al.  IkappaB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a. , 2004, Cell.

[46]  E. Lam,et al.  Gefitinib (Iressa) represses FOXM1 expression via FOXO3a in breast cancer , 2009, Molecular Cancer Therapeutics.

[47]  Peng Huang,et al.  The Warburg effect and its cancer therapeutic implications , 2007, Journal of bioenergetics and biomembranes.

[48]  Ruiwen Wang,et al.  Selenium sensitizes MCF-7 breast cancer cells to doxorubicin-induced apoptosis through modulation of phospho-Akt and its downstream substrates , 2007, Molecular Cancer Therapeutics.

[49]  G. Mills,et al.  ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation , 2008, Nature Cell Biology.

[50]  Guido Kroemer,et al.  Autophagy and the integrated stress response. , 2010, Molecular cell.

[51]  S. Narod,et al.  Triple-Negative Breast Cancer: Clinical Features and Patterns of Recurrence , 2007, Clinical Cancer Research.

[52]  S. Andò,et al.  The estrogen receptor α is the key regulator of the bifunctional role of FoxO3a transcription factor in breast cancer motility and invasiveness , 2013, Cell cycle.

[53]  P. Das,et al.  18β‐glycyrrhetinic acid induces apoptosis through modulation of Akt/FOXO3a/Bim pathway in human breast cancer MCF‐7 cells , 2012, Journal of cellular physiology.

[54]  Domenico Coppola,et al.  MicroRNA-155 Regulates Cell Survival, Growth, and Chemosensitivity by Targeting FOXO3a in Breast Cancer* , 2010, The Journal of Biological Chemistry.

[55]  F. Soares,et al.  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 , 2013, BMC Cancer.

[56]  G. Sonenshein,et al.  Forkhead Box Transcription Factor FOXO3a Regulates Estrogen Receptor Alpha Expression and Is Repressed by the Her-2/neu/Phosphatidylinositol 3-Kinase/Akt Signaling Pathway , 2004, Molecular and Cellular Biology.

[57]  R. Coombes,et al.  Paclitaxel-induced nuclear translocation of FOXO3a in breast cancer cells is mediated by c-Jun NH2-terminal kinase and Akt. , 2006, Cancer research.

[58]  L. Cantley,et al.  Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation , 2009, Science.