title: Transcriptome- and proteome-oriented identification of dysregulated eIF4G, STAT3, and Hippo pathways altered by PIK3CAH1047Rin HER2/ER-positive breast cancer.
abstract: Phosphatidylinositol 3-kinase (PI3K)/AKT pathway aberrations are common in human breast cancer. Furthermore, PIK3CA mutations are commonly associated with resistance to anti-epidermal growth factor receptor 2 (HER2) or anti-estrogen receptor (ER) agents in HER2 or ER positive (HER2+/ER+) breast cancer. Hence, deciphering the underlying mechanisms of PIK3CA mutations in HER2+/ER+breast cancer would provide novel insights into elucidating resistance to anti-HER2/ER therapies.
  
  
  
  In this study, we systematically investigated the biological consequences of PIK3CAH1047Rin HER2+/ER+breast cancer by uniquely incorporating mRNA transcriptomic data from The Cancer Genome Atlas and proteomic data from reverse-phase protein arrays.
  
  
  
  Our integrative bioinformatics analyses revealed that several important pathways such as STAT3 and VEGF/hypoxia were selectively altered by PIK3CAH1047Rin HER2+/ER+breast cancer. Protein differential expression analysis indicated that an elevated eIF4G might promote tumor angiogenesis and growth via regulation of the hypoxia-activated switch in HER2+PIK3CAH1047Rbreast cancer. We observed hypo-phosphorylation of EGFR in HER2+PIK3CAH1047Rbreast cancer versus HER2+PIK3CAwild-type(PIK3CAWT). In addition, ER and PIK3CAH1047Rmight cooperate to activate STAT3, MAPK, AKT, and Hippo pathways in ER+PIK3CAH1047Rbreast cancer. A higher YAPpS127level was observed in ER+PIK3CAH1047Rpatients than that in an ER+PIK3CAWTsubgroup. By examining breast cancer cell lines having both microarray gene expression and drug treatment data from the Genomics of Drug Sensitivity in Cancer and the Stand Up to Cancer datasets, we found that the elevated YAP1 mRNA expression was associated with the resistance of BCL-2 family inhibitors, but with the sensitivity to MEK/MAPK inhibitors in breast cancer cells.
  
  
  
  In summary, these findings shed light on the functional consequences of PIK3CAH1047R-driven breast tumorigenesis and resistance to the existing therapeutic agents in HER2+/ER+breast cancer.
authors: Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, 37203, USA.|Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02215, USA.|Center for Complex Networks Research, Northeastern University, Boston, MA, 02115, USA.
authors: Feixiong
authors: F
authors: Cheng
authors: Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, 37203, USA.|Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.
authors: Junfei
authors: J
authors: Zhao
authors: Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
authors: Ariella B
authors: AB
authors: Hanker
authors: Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
authors: Monica Red
authors: MR
authors: Brewer
authors: Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, 37232, USA. carlos.arteaga@vanderbilt.edu.|Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, 37232, USA. carlos.arteaga@vanderbilt.edu.|Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, 37232, USA. carlos.arteaga@vanderbilt.edu.
authors: Carlos L
authors: CL
authors: Arteaga
authors: Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, 37203, USA. zhongming.zhao@uth.tmc.edu.|Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA. zhongming.zhao@uth.tmc.edu.|Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, 37232, USA. zhongming.zhao@uth.tmc.edu.|Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, 37232, USA. zhongming.zhao@uth.tmc.edu.
authors: Zhongming
authors: Z
authors: Zhao
mesh_terms: D015415:Biomarkers; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics*; D016000:Cluster Analysis; D019295:Computational Biology / Q000379:methods; D030541:Databases, Genetic; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D039603:Eukaryotic Initiation Factor-4G / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D000090683:Hippo Signaling Pathway; D006801:Humans; D058990:Molecular Targeted Therapy; D009154:Mutation; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D040901:Proteomics / Q000379:methods; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D011960:Receptors, Estrogen / Q000235:genetics*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D015415:Biomarkers; D058534:Class I Phosphatidylinositol 3-Kinases; D039603:Eukaryotic Initiation Factor-4G; D017346:Protein Serine-Threonine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D050796:STAT3 Transcription Factor; C484760:PIK3CA protein, human
keywords: Bioinformatics; Breast cancer; ER; HER2; PIK3CA; Synergistic interactions