title: Extensive analysis of signaling pathway molecules in breast cancer: association with clinicopathological characteristics.
abstract: BACKGROUND
  The aim of this study was to extensively analyze the signaling pathway molecules in breast cancer and to explore candidate biomarkers for clinicopathological relevance.
  
  
  METHODS
  We assessed the expression of key factors in cell signaling, namely p-AKT, cyclin D1, P27, p-p70S6 K, p-4EBP1, and p-MAPK/ERK, within 338 invasive breast cancer patients. These factors were immunohistochemically examined in tumor tissues and assessed by staining score. Staining scores were analyzed by a clustering method to devise a new classification based on pathway activity. We investigated the relationships among staining scores, the clustering classification, and patient characteristics.
  
  
  RESULTS
  The proportion of patients displaying high expression levels were as follows: p-AKT, 75%; cyclin D1, 12%; P27, 53%; p-p70S6 K, 37%; p-4EBP1, 19%; and p-MAPK/ERK, 3%. Patients were classified into two groups on the basis of staining scores. Group 1 (39%) included more positive cases for p-4EBP1, p-MAPK/ERK, and p-p70S6 K and fewer positive cases for P27 and cyclin D1 than Group 2 (61%). The clustering classification was significantly related to subgrouping by hormone receptor and HER2 (P < 0.001), nuclear grade (P < 0.001) and histological subtype (P = 0.034). A strong positive correlation was identified between p-AKT and P27, cyclin D1 and P27, p-p70S6 K and p-4EBP1, p-p70S6 K and p-MAPK/ERK, and between p-4EBP1 and p-MAPK/ERK. Levels of p-p70S6 K were significantly related to recurrence in both univariate (RR = 0.75, P < 0.001) and multivariate (RR = 0.71, P = 0.049) analyses.
  
  
  CONCLUSIONS
  The present study helps us to understand the characteristics of signaling pathway status in breast cancers. Moreover, p-p70S6 K expression may be of use in predicting clinical outcome.
authors.affiliation: Department of Pathology, Cancer Institute, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan, rhorii-pathology@jfcr.or.jp.
authors.forename: Rie
authors.initials: R
authors.lastname: Horii
authors.forename: Masaaki
authors.initials: M
authors.lastname: Matsuura
authors.forename: Shingo
authors.initials: S
authors.lastname: Dan
authors.forename: Masaru
authors.initials: M
authors.lastname: Ushijima
authors.forename: Natsue
authors.initials: N
authors.lastname: Uehiro
authors.forename: Akiko
authors.initials: A
authors.lastname: Ogiya
authors.forename: Naoko
authors.initials: N
authors.lastname: Honma
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Ito
authors.forename: Takuji
authors.initials: T
authors.lastname: Iwase
authors.forename: Takao
authors.initials: T
authors.lastname: Yamori
authors.forename: Futoshi
authors.initials: F
authors.lastname: Akiyama
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000502:physiology; D001943:Breast Neoplasms / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy; D018797:Cell Cycle Proteins; D019938:Cyclin D1 / Q000096:biosynthesis; D048049:Extracellular Signal-Regulated MAP Kinases / Q000096:biosynthesis; D005260:Female; D006801:Humans; D008875:Middle Aged; D010750:Phosphoproteins / Q000096:biosynthesis; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000096:biosynthesis*; D015398:Signal Transduction / Q000502:physiology*; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; C530104:CCND1 protein, human; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D010750:Phosphoproteins; D018809:Proliferating Cell Nuclear Antigen; C413374:p27 antigen; D019938:Cyclin D1; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D048049:Extracellular Signal-Regulated MAP Kinases