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Jean Zhao, PhD


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Researcher

  • Professor of Biological Chemistry and Molecular Pharmacology, Harvard Medical School

Contact Information

  • Office Phone Number617-632-2932

Bio

Jean Zhao received her PhD from Tufts University School of Medicine in 1999. She did her postdoctoral work in the laboratory of Dr. Thomas M. Roberts, became an Instructor in Medicine at Harvard Medical School in 2003, and joined the faculty of DFCI and Harvard Medical School in 2006.

Research

Kinase signaling in cancer

We are interested in how kinases in general, and phosphatidylinositol 3-kinases (PI3K) in particular, control malignant transformation. The work of our laboratory integrates molecular biology, tissue engineering and novel mouse models of human cancer to study oncogenic alterations in kinases that are involved in primary tumor formation and metastasis. In addition to our unique genetically engineered mouse models, we have developed a number of additional experimental systems, including, synthetic human tumors, and kinome-wide libraries of activated kinases to elucidate the mechanisms by which kinases function in cancer. We hope our studies will allow us to harness the potential of these molecules as specific targets for cancer therapies.

The role of the PIK3CA gene in the development and aging of the brain. Sci Rep. 2021 01 11; 11(1):291.
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CDK4/6 inhibition reprograms the breast cancer enhancer landscape by stimulating AP-1 transcriptional activity. Nat Cancer. 2021 Jan; 2(1):34-48.
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Divergent Roles of PI3K Isoforms in PTEN-Deficient Glioblastomas. Cell Rep. 2020 09 29; 32(13):108196.
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PIK3CA C-terminal frameshift mutations are novel oncogenic events that sensitize tumors to PI3K-a inhibition. Proc Natl Acad Sci U S A. 2020 09 29; 117(39):24427-24433.
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A sequential methodology for the rapid identification and characterization of breast cancer-associated functional SNPs. Nat Commun. 2020 07 03; 11(1):3340.
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Integrating Immunotherapy and Targeted Therapy in Cancer Treatment: Mechanistic Insights and Clinical Implications. Clin Cancer Res. 2020 11 01; 26(21):5557-5566.
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Limited Environmental Serine and Glycine Confer Brain Metastasis Sensitivity to PHGDH Inhibition. Cancer Discov. 2020 09; 10(9):1352-1373.
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Increased lysosomal biomass is responsible for the resistance of triple-negative breast cancers to CDK4/6 inhibition. Sci Adv. 2020 Jun; 6(25):eabb2210.
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High-throughput dynamic BH3 profiling may quickly and accurately predict effective therapies in solid tumors. Sci Signal. 2020 06 16; 13(636).
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Inhibition of the transcriptional kinase CDK7 overcomes therapeutic resistance in HER2-positive breast cancers. Oncogene. 2020 01; 39(1):50-63.
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PI3 kinase alpha and delta promote hematopoietic stem cell activation. JCI Insight. 2019 05 23; 5.
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Buparlisib in Patients With Recurrent Glioblastoma Harboring Phosphatidylinositol 3-Kinase Pathway Activation: An Open-Label, Multicenter, Multi-Arm, Phase II Trial. J Clin Oncol. 2019 03 20; 37(9):741-750.
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Improving orthotopic mouse models of patient-derived breast cancer brain metastases by a modified intracarotid injection method. Sci Rep. 2019 01 24; 9(1):622.
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PARP Inhibition Elicits STING-Dependent Antitumor Immunity in Brca1-Deficient Ovarian Cancer. Cell Rep. 2018 12 11; 25(11):2972-2980.e5.
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Targeted Profiling of RNA Translation. Curr Protoc Mol Biol. 2019 01; 125(1):e71.
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A Conditional Dependency on MELK for the Proliferation of Triple-Negative Breast Cancer Cells. iScience. 2018 Nov 30; 9:149-160.
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Structure-Based Drug Design and Identification of H2O-Soluble and Low Toxic Hexacyclic Camptothecin Derivatives with Improved Efficacy in Cancer and Lethal Inflammation Models in Vivo. J Med Chem. 2018 10 11; 61(19):8613-8624.
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BRCA1-IRIS promotes human tumor progression through PTEN blockade and HIF-1a activation. Proc Natl Acad Sci U S A. 2018 10 09; 115(41):E9600-E9609.
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Targeted profiling of RNA translation reveals mTOR-4EBP1/2-independent translation regulation of mRNAs encoding ribosomal proteins. Proc Natl Acad Sci U S A. 2018 10 02; 115(40):E9325-E9332.
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An alternative splicing switch in FLNB promotes the mesenchymal cell state in human breast cancer. Elife. 2018 07 30; 7.
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CDK4/6 Inhibition in Cancer: Beyond Cell Cycle Arrest. Trends Cell Biol. 2018 11; 28(11):911-925.
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Dual HDAC and PI3K Inhibition Abrogates NF?B- and FOXM1-Mediated DNA Damage Response to Radiosensitize Pediatric High-Grade Gliomas. Cancer Res. 2018 07 15; 78(14):4007-4021.
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Correction: MELK is an oncogenic kinase essential for mitotic progression in basal-like breast cancer cells. Elife. 2018 03 12; 7.
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Isoform-Selective Phosphatidylinositol 3-Kinase Inhibition in Cancer. J Clin Oncol. 2018 05 01; 36(13):1339-1342.
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Oncogenic Kinase-Induced PKM2 Tyrosine 105 Phosphorylation Converts Nononcogenic PKM2 to a Tumor Promoter and Induces Cancer Stem-like Cells. Cancer Res. 2018 05 01; 78(9):2248-2261.
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Allele-Specific Chromatin Recruitment and Therapeutic Vulnerabilities of ESR1 Activating Mutations. Cancer Cell. 2018 02 12; 33(2):173-186.e5.
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Drug Resistance in HER2-Positive Breast Cancer Brain Metastases: Blame the Barrier or the Brain? Clin Cancer Res. 2018 04 15; 24(8):1795-1804.
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Oridonin inhibits aberrant AKT activation in breast cancer. Oncotarget. 2018 May 08; 9(35):23878-23889.
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Pik3ca is required for mouse uterine gland development and pregnancy. PLoS One. 2018; 13(1):e0191433.
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PI3Ka inactivation in leptin receptor cells increases leptin sensitivity but disrupts growth and reproduction. JCI Insight. 2017 12 07; 2(23).
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Targeting neuronal activity-regulated neuroligin-3 dependency in high-grade glioma. Nature. 2017 09 28; 549(7673):533-537.
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MELK is not necessary for the proliferation of basal-like breast cancer cells. Elife. 2017 09 19; 6.
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CDK4/6 inhibition triggers anti-tumour immunity. Nature. 2017 08 24; 548(7668):471-475.
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CRKL Mediates p110ß-Dependent PI3K Signaling in PTEN-Deficient Cancer Cells. Cell Rep. 2017 07 18; 20(3):549-557.
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PI3K-p110a mediates the oncogenic activity induced by loss of the novel tumor suppressor PI3K-p85a. Proc Natl Acad Sci U S A. 2017 07 03; 114(27):7095-7100.
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Cell-Cycle-Targeting MicroRNAs as Therapeutic Tools against Refractory Cancers. Cancer Cell. 2017 04 10; 31(4):576-590.e8.
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The emerging role of PI3K/AKT-mediated epigenetic regulation in cancer. Biochim Biophys Acta Rev Cancer. 2017 Aug; 1868(1):123-131.
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Targeting of Ras-mediated FGF signaling suppresses Pten-deficient skin tumor. Proc Natl Acad Sci U S A. 2016 11 15; 113(46):13156-13161.
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Rac1-mediated membrane raft localization of PI3K/p110ß is required for its activation by GPCRs or PTEN loss. Elife. 2016 10 04; 5.
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NTRK2 activation cooperates with PTEN deficiency in T-ALL through activation of both the PI3K-AKT and JAK-STAT3 pathways. Cell Discov. 2016; 2:16030.
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Mitotic MELK-eIF4B signaling controls protein synthesis and tumor cell survival. Proc Natl Acad Sci U S A. 2016 08 30; 113(35):9810-5.
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CDK4/6 inhibition: the late harvest cycle begins. Oncotarget. 2016 08 02; 7(31):48854-48856.
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Discovery of a Series of 5,11-Dihydro-6H-benzo[e]pyrimido[5,4-b][1,4]diazepin-6-ones as Selective PI3K-d/? Inhibitors. ACS Med Chem Lett. 2016 Oct 13; 7(10):908-912.
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Combined inhibition of PI3K and PARP is effective in the treatment of ovarian cancer cells with wild-type PIK3CA genes. Gynecol Oncol. 2016 09; 142(3):548-56.
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Tyrosine receptor kinase B is a drug target in astrocytomas. Neuro Oncol. 2017 01; 19(1):22-30.
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PI3K/AKT Signaling Regulates H3K4 Methylation in Breast Cancer. Cell Rep. 2016 06 21; 15(12):2692-704.
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Combination inhibition of PI3K and mTORC1 yields durable remissions in mice bearing orthotopic patient-derived xenografts of HER2-positive breast cancer brain metastases. Nat Med. 2016 07; 22(7):723-6.
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A cell-based quantitative high-throughput image screening identified novel autophagy modulators. Pharmacol Res. 2016 08; 110:35-49.
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PI3K in the ventromedial hypothalamic nucleus mediates estrogenic actions on energy expenditure in female mice. Sci Rep. 2016 Mar 18; 6:23459.
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Effective use of PI3K inhibitor BKM120 and PARP inhibitor Olaparib to treat PIK3CA mutant ovarian cancer. Oncotarget. 2016 Mar 15; 7(11):13153-66.
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Overcoming Therapeutic Resistance in HER2-Positive Breast Cancers with CDK4/6 Inhibitors. Cancer Cell. 2016 Mar 14; 29(3):255-269.
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Corrigendum: Essential roles of PI(3)K-p110ß in cell growth, metabolism and tumorigenesis. Nature. 2016 05 12; 533(7602):278.
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Mouse models of human PIK3CA-related brain overgrowth have acutely treatable epilepsy. Elife. 2015 Dec 03; 4.
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Modeling human PIK3CA-related congenital brain overgrowth and epilepsy in mice. Int J Dev Neurosci. 2015 Dec; 47(Pt A):46.
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A PI3K p110ß-Rac signalling loop mediates Pten-loss-induced perturbation of haematopoiesis and leukaemogenesis. Nat Commun. 2015 Oct 07; 6:8501.
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CDK7-dependent transcriptional addiction in triple-negative breast cancer. Cell. 2015 Sep 24; 163(1):174-86.
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The ERa-PI3K Cascade in Proopiomelanocortin Progenitor Neurons Regulates Feeding and Glucose Balance in Female Mice. Endocrinology. 2015 Dec; 156(12):4474-91.
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Bioprinting for cancer research. Trends Biotechnol. 2015 Sep; 33(9):504-13.
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Light-triggered, self-immolative nucleic Acid-drug nanostructures. J Am Chem Soc. 2015 May 20; 137(19):6112-5.
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Class IA Phosphatidylinositol 3-Kinase Isoform p110a Mediates Vascular Remodeling. Arterioscler Thromb Vasc Biol. 2015 Jun; 35(6):1434-44.
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Chemopreventive effects of aspirin at a glance. Biochim Biophys Acta. 2015 Apr; 1855(2):254-63.
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Role of phosphoinositide 3-OH kinase p110ß in skeletal myogenesis. Mol Cell Biol. 2015 Apr; 35(7):1182-96.
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PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutic targeting. Nat Rev Cancer. 2015 Jan; 15(1):7-24.
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Measurement of PIP3 levels reveals an unexpected role for p110ß in early adaptive responses to p110a-specific inhibitors in luminal breast cancer. Cancer Cell. 2015 Jan 12; 27(1):97-108.
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Cyclin C is a haploinsufficient tumour suppressor. Nat Cell Biol. 2014 Nov; 16(11):1080-91.
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MELK is an oncogenic kinase essential for mitotic progression in basal-like breast cancer cells. Elife. 2014 May 20; 3:e01763.
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PI3K isoform dependence of PTEN-deficient tumors can be altered by the genetic context. Proc Natl Acad Sci U S A. 2014 Apr 29; 111(17):6395-400.
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Hematopoiesis and RAS-driven myeloid leukemia differentially require PI3K isoform p110a. J Clin Invest. 2014 Apr; 124(4):1794-809.
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A genetic mouse model of invasive endometrial cancer driven by concurrent loss of Pten and Lkb1 Is highly responsive to mTOR inhibition. Cancer Res. 2014 Jan 01; 74(1):15-23.
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The gene dosage of class Ia PI3K dictates the development of PTEN hamartoma tumor syndrome. . 2013 Dec 01; 12(23):3589-93.
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Coordinate activation of Shh and PI3K signaling in PTEN-deficient glioblastoma: new therapeutic opportunities. Nat Med. 2013 Nov; 19(11):1518-23.
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Mutant PIK3CA accelerates HER2-driven transgenic mammary tumors and induces resistance to combinations of anti-HER2 therapies. Proc Natl Acad Sci U S A. 2013 Aug 27; 110(35):14372-7.
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Spatially distinct roles of class Ia PI3K isoforms in the development and maintenance of PTEN hamartoma tumor syndrome. Genes Dev. 2013 Jul 15; 27(14):1568-80.
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Central GLP-2 enhances hepatic insulin sensitivity via activating PI3K signaling in POMC neurons. Cell Metab. 2013 Jul 02; 18(1):86-98.
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Conditional loss of ErbB3 delays mammary gland hyperplasia induced by mutant PIK3CA without affecting mammary tumor latency, gene expression, or signaling. Cancer Res. 2013 Jul 01; 73(13):4075-85.
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Opposing effects of androgen deprivation and targeted therapy on prostate cancer prevention. Cancer Discov. 2013 Jan; 3(1):44-51.
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The p110a and p110ß isoforms of PI3K play divergent roles in mammary gland development and tumorigenesis. Genes Dev. 2012 Jul 15; 26(14):1573-86.
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Functional characterization of an isoform-selective inhibitor of PI3K-p110ß as a potential anticancer agent. Cancer Discov. 2012 May; 2(5):425-33.
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Kinome-wide selectivity profiling of ATP-competitive mammalian target of rapamycin (mTOR) inhibitors and characterization of their binding kinetics. J Biol Chem. 2012 Mar 23; 287(13):9742-9752.
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Lysosomal transmembrane protein LAPTM4B promotes autophagy and tolerance to metabolic stress in cancer cells. Cancer Res. 2011 Dec 15; 71(24):7481-9.
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The acute effects of leptin require PI3K signaling in the hypothalamic ventral premammillary nucleus. J Neurosci. 2011 Sep 14; 31(37):13147-56.
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Oncogenic PIK3CA-driven mammary tumors frequently recur via PI3K pathway-dependent and PI3K pathway-independent mechanisms. Nat Med. 2011 Aug 07; 17(9):1116-20.
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Therapeutic implications of GIPC1 silencing in cancer. PLoS One. 2010 Dec 30; 5(12):e15581.
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COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature. 2010 Dec 16; 468(7326):968-72.
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PI3K signaling in the ventromedial hypothalamic nucleus is required for normal energy homeostasis. Cell Metab. 2010 Jul 07; 12(1):88-95.
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Specific roles of the p110alpha isoform of phosphatidylinsositol 3-kinase in hepatic insulin signaling and metabolic regulation. Cell Metab. 2010 Mar 03; 11(3):220-30.
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Estrogen receptor-negative breast cancer: new insights into subclassification and targeting. Clin Cancer Res. 2009 Oct 15; 15(20):6309-10.
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Phosphatidyl inositol 3-kinase signaling in hypothalamic proopiomelanocortin neurons contributes to the regulation of glucose homeostasis. Endocrinology. 2009 Nov; 150(11):4874-82.
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Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov. 2009 Aug; 8(8):627-44.
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SIK1 couples LKB1 to p53-dependent anoikis and suppresses metastasis. Sci Signal. 2009 Jul 21; 2(80):ra35.
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3-Phosphoinositide-dependent kinase 1 potentiates upstream lesions on the phosphatidylinositol 3-kinase pathway in breast carcinoma. Cancer Res. 2009 Aug 01; 69(15):6299-306.
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Should individual PI3 kinase isoforms be targeted in cancer? Curr Opin Cell Biol. 2009 Apr; 21(2):199-208.
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Essential roles of PI(3)K-p110beta in cell growth, metabolism and tumorigenesis. Nature. 2008 Aug 07; 454(7205):776-9.
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Integrative genomic approaches identify IKBKE as a breast cancer oncogene. Cell. 2007 Jun 15; 129(6):1065-79.
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Surveillance mechanism linking Bub1 loss to the p53 pathway. Proc Natl Acad Sci U S A. 2007 May 15; 104(20):8334-9.
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The p110alpha isoform of phosphatidylinositol 3-kinase is essential for polyomavirus middle T antigen-mediated transformation. J Virol. 2007 Jul; 81(13):7069-76.
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PI3 kinases in cancer: from oncogene artifact to leading cancer target. Sci STKE. 2006 Dec 12; 2006(365):pe52.
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The p110alpha isoform of PI3K is essential for proper growth factor signaling and oncogenic transformation. Proc Natl Acad Sci U S A. 2006 Oct 31; 103(44):16296-300.
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The oncogenic properties of mutant p110alpha and p110beta phosphatidylinositol 3-kinases in human mammary epithelial cells. Proc Natl Acad Sci U S A. 2005 Dec 20; 102(51):18443-8.
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A genetic screen for candidate tumor suppressors identifies REST. Cell. 2005 Jun 17; 121(6):837-48.
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Androgen-induced differentiation and tumorigenicity of human prostate epithelial cells. Cancer Res. 2004 Dec 15; 64(24):8867-75.
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Functional genetics and experimental models of human cancer. Trends Mol Med. 2004 Jul; 10(7):344-50.
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Simian virus 40 large T antigen targets the spindle assembly checkpoint protein Bub1. Proc Natl Acad Sci U S A. 2004 Jan 27; 101(4):947-52.
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A chemical genetic screen identifies inhibitors of regulated nuclear export of a Forkhead transcription factor in PTEN-deficient tumor cells. Cancer Cell. 2003 Dec; 4(6):463-76.
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Human mammary epithelial cell transformation through the activation of phosphatidylinositol 3-kinase. Cancer Cell. 2003 May; 3(5):483-95.
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