title: BRCA Mutation-Related and Claudin-Low Breast Cancer: Blood Relatives or Stepsisters.
abstract: BACKGROUND
  BRCA mutation-associated (BRCAmut) breast cancer represents a heterogeneous group displaying certain molecular features. Claudin-low breast cancers (CLBC) overlap with characteristics of BRCAmut tumors; therefore, we have investigated whether these are identical subtypes.
  
  
  METHODS
  Using public gene expression data, CLDN, CDH1, 9-cell line claudin-low predictor (9CLCLP) and PAM50 expression was evaluated in BRCAmut and BRCA wild-type (BRCAwt) breast cancer cases focusing on their possible overlap with the CLBC subtype. A separate formalin-fixed, paraffin-embedded (FFPE) cohort of 22 BRCAmut and 19 BRCAwt tumor tissues was used for immunohistochemical examination of AR, CD24, CD44, CK5/6, claudin-1, -3, -4 and -7, E-cadherin, EGFR, estrogen receptor (ER), EZH2, HER2, Ki67, p53, progesterone receptor (PgR) and vimentin expression.
  
  
  RESULTS
  In the data sets, CLDN1 (ROC = 0.785, p < 0.001), CDH1 (ROC = 0.785, p < 0.001), CLDN7 (ROC = 0.723, p < 0.001), CLDN3 (ROC = 0.696, p = 0.020) and CLDN4 (ROC = 0.685, p = 0.027) were expressed at higher level in BRCAmut than BRCAwt tumor tissue. The PAM50 subtype differed from the assigned immunohistochemistry (IHC)-based subtype in 30%. Based on accessible 9CLCLP predictor genes, BRCAmut breast cancer does not display the claudin-low phenotype. Utilizing FFPE samples, claudins were evidently expressed in both BRCAmut and BRCAwt cases. However, at the protein level, only claudin-3 expression was higher in BRCAmut tumors, while claudin-1, -4 and -7 and E-cadherin expression was lower compared to BRCAwt cases. A CD24low/CD44high phenotype was found in BRCAmut tumors upon comparison with BRCAwt cases (p < 0.001 and p = 0.001, respectively).
  
  
  CONCLUSIONS
  There is a prominent correlation between the genes under focus herein and BRCA mutation status. BRCAmut tumors bear stem cell characteristics displaying a distinct cell adhesion molecule profile characterized by high expression of CDH1 and CLDN4 according to public gene expression data set analysis, and higher claudin-3 expression as detected by IHC; thus, BRCAmut breast carcinomas are not identical with the previously identified claudin-low subtype of breast cancer.
authors.affiliation: Second Department of Pathology, Semmelweis University, Budapest, Hungary.
authors.forename: Lilla
authors.initials: L
authors.lastname: Madaras
authors.forename: Nora
authors.initials: N
authors.lastname: Balint
authors.forename: Balazs
authors.initials: B
authors.lastname: Gyorffy
authors.forename: Anna-Maria
authors.initials: AM
authors.lastname: Tokes
authors.forename: Iris
authors.initials: I
authors.lastname: Barshack
authors.forename: Ady
authors.initials: A
authors.lastname: Yosepovich
authors.forename: Eitan
authors.initials: E
authors.lastname: Friedman
authors.forename: Shani
authors.initials: S
authors.lastname: Paluch-Shimon
authors.forename: Dov
authors.initials: D
authors.lastname: Zippel
authors.forename: Kornelia
authors.initials: K
authors.lastname: Baghy
authors.forename: Jozsef
authors.initials: J
authors.lastname: Timar
authors.forename: Ilona
authors.initials: I
authors.lastname: Kovalszky
authors.forename: Janina
authors.initials: J
authors.lastname: Kulka
authors.forename: Attila Marcell
authors.initials: AM
authors.lastname: Szasz
mesh_terms: D000328:Adult; D000368:Aged; D015703:Antigens, CD; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000145:classification* / Q000235:genetics*; D015820:Cadherins / Q000235:genetics*; D018270:Carcinoma, Ductal, Breast / Q000235:genetics; D062465:Claudin-3 / Q000235:genetics; D062506:Claudin-4 / Q000235:genetics; D057167:Claudins / Q000235:genetics*; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D011960:Receptors, Estrogen / Q000235:genetics; D011980:Receptors, Progesterone / Q000235:genetics; D014746:Vimentin / Q000235:genetics
chemical_list: D015703:Antigens, CD; D014408:Biomarkers, Tumor; C513384:CDH1 protein, human; C568157:CLDN4 protein, human; D015820:Cadherins; D062465:Claudin-3; D062506:Claudin-4; D057167:Claudins; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D014746:Vimentin