title: The molecular landscape of premenopausal breast cancer.
abstract: BACKGROUND
  Breast cancer in premenopausal women (preM) is frequently associated with worse prognosis compared to that in postmenopausal women (postM), and there is evidence that preM estrogen receptor-positive (ER+) tumors may respond poorly to endocrine therapy. There is, however, a paucity of studies characterizing molecular alterations in premenopausal tumors, a potential avenue for personalizing therapy for this group of women.
  
  
  METHODS
  Using TCGA and METABRIC databases, we analyzed gene expression, copy number, methylation, somatic mutation, and reverse-phase protein array data in breast cancers from >2,500 preM and postM women.
  
  
  RESULTS
  PreM tumors showed unique gene expression compared to postM tumors, however, this difference was limited to ER+ tumors. ER+ preM tumors showed unique DNA methylation, copy number and somatic mutations. Integrative pathway analysis revealed that preM tumors had elevated integrin/laminin and EGFR signaling, with enrichment for upstream TGFβ-regulation. Finally, preM tumors showed three different gene expression clusters with significantly different outcomes.
  
  
  CONCLUSIONS
  Together these data suggest that ER+ preM tumors have distinct molecular characteristics compared to ER+ postM tumors, particularly with respect to integrin/laminin and EGFR signaling, which may represent therapeutic targets in this subgroup of breast cancers.
authors.affiliation: Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA. liaoge.serena@gmail.com.
authors.forename: Serena
authors.initials: S
authors.lastname: Liao
authors.affiliation: Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA. hartmaierr@upmc.edu.|Womens Cancer Research Center, Magee-Womens Research Institute and University of Pittsburgh Cancer Institute, 204 Craft Avenue, Pittsburgh, PA, 15213, USA. hartmaierr@upmc.edu.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Hartmaier
authors.affiliation: Womens Cancer Research Center, Magee-Womens Research Institute and University of Pittsburgh Cancer Institute, 204 Craft Avenue, Pittsburgh, PA, 15213, USA. mcguirek2@mail.magee.edu.|Department of Surgery University of Pittsburgh Cancer Center UPCI, Pittsburgh, PA, USA. mcguirek2@mail.magee.edu.
authors.forename: Kandace P
authors.initials: KP
authors.lastname: McGuire
authors.affiliation: Womens Cancer Research Center, Magee-Womens Research Institute and University of Pittsburgh Cancer Institute, 204 Craft Avenue, Pittsburgh, PA, 15213, USA. puhallasl@mail.magee.edu.|Department of Medicine, Division of Hematology/Oncology, Pittsburgh, PA, USA. puhallasl@mail.magee.edu.
authors.forename: Shannon L
authors.initials: SL
authors.lastname: Puhalla
authors.affiliation: Womens Cancer Research Center, Magee-Womens Research Institute and University of Pittsburgh Cancer Institute, 204 Craft Avenue, Pittsburgh, PA, 15213, USA. sol23@pitt.edu.|Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, PA, USA. sol23@pitt.edu.
authors.forename: Soumya
authors.initials: S
authors.lastname: Luthra
authors.affiliation: Womens Cancer Research Center, Magee-Womens Research Institute and University of Pittsburgh Cancer Institute, 204 Craft Avenue, Pittsburgh, PA, 15213, USA. chandranur@upmc.edu.|Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, PA, USA. chandranur@upmc.edu.
authors.forename: Uma R
authors.initials: UR
authors.lastname: Chandran
authors.affiliation: Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA. tianzhou.ma0105@gmail.com.
authors.forename: Tianzhou
authors.initials: T
authors.lastname: Ma
authors.affiliation: Department of Pathology Magee-Womens Hospital, Pittsburgh, PA, USA. rbhargava@mail.magee.edu.
authors.forename: Rohit
authors.initials: R
authors.lastname: Bhargava
authors.affiliation: Womens Cancer Research Center, Magee-Womens Research Institute and University of Pittsburgh Cancer Institute, 204 Craft Avenue, Pittsburgh, PA, 15213, USA. fm@cs.cmu.edu.|Department of Obstetrics, Gynecology and Reproductive Sciences, Division of Gynecologic Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. fm@cs.cmu.edu.|Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA. fm@cs.cmu.edu.
authors.forename: Francesmary
authors.initials: F
authors.lastname: Modugno
authors.affiliation: Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA. davidsonne@upmc.edu.|Womens Cancer Research Center, Magee-Womens Research Institute and University of Pittsburgh Cancer Institute, 204 Craft Avenue, Pittsburgh, PA, 15213, USA. davidsonne@upmc.edu.
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Davidson
authors.affiliation: Five3 Genomics, LLC, Santa Cruz, CA, USA. steve@five3genomics.com.
authors.forename: Steve
authors.initials: S
authors.lastname: Benz
authors.affiliation: Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA. leeav@upmc.edu.|Womens Cancer Research Center, Magee-Womens Research Institute and University of Pittsburgh Cancer Institute, 204 Craft Avenue, Pittsburgh, PA, 15213, USA. leeav@upmc.edu.
authors.forename: Adrian V
authors.initials: AV
authors.lastname: Lee
authors.affiliation: Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA. ctseng@pitt.edu.|Department of Computational Biology, University of Pittsburgh, Pittsburgh, PA, USA. ctseng@pitt.edu.|Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA. ctseng@pitt.edu.
authors.forename: George C
authors.initials: GC
authors.lastname: Tseng
authors.affiliation: Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA. oesterreichs@upmc.edu.|Womens Cancer Research Center, Magee-Womens Research Institute and University of Pittsburgh Cancer Institute, 204 Craft Avenue, Pittsburgh, PA, 15213, USA. oesterreichs@upmc.edu.
authors.forename: Steffi
authors.initials: S
authors.lastname: Oesterreich
mesh_terms: D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics*; D016000:Cluster Analysis; D019295:Computational Biology; D056915:DNA Copy Number Variations; D019175:DNA Methylation; D030541:Databases, Genetic; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D009154:Mutation; D017063:Outcome Assessment, Health Care; D017698:Postmenopause; D017697:Premenopause; D011379:Prognosis; D040901:Proteomics; D015203:Reproducibility of Results; D015398:Signal Transduction
chemical_list: D014408:Biomarkers, Tumor