Claudin-Low Breast Cancer; Clinical & Pathological Characteristics

PLoS One. 2017 Jan 3;12(1):e0168669. doi: 10.1371/journal.pone.0168669. eCollection 2017.

Abstract

Claudin-low breast cancer is a molecular type of breast cancer originally identified by gene expression profiling and reportedly associated with poor survival. Claudin-low tumors have been recognised to preferentially display a triple-negative phenotype, however only a minority of triple-negative breast cancers are claudin-low. We sought to identify an immunohistochemical profile for claudin-low tumors that could facilitate their identification in formalin fixed paraffin embedded tumor material. First, an in silico collection of ~1600 human breast cancer expression profiles was assembled and all claudin-low tumors identified. Second, genes differentially expressed between claudin-low tumors and all other molecular subtypes of breast cancer were identified. Third, a number of these top differentially expressed genes were tested using immunohistochemistry for expression in a diverse panel of breast cancer cell lines to determine their specificity for claudin-low tumors. Finally, the immunohistochemical panel found to be most characteristic of claudin-low tumors was examined in a cohort of 942 formalin fixed paraffin embedded human breast cancers with >10 years clinical follow-up to evaluate the clinico-pathologic and survival characteristics of this tumor subtype. Using this approach we determined that claudin-low breast cancer is typically negative for ER, PR, HER2, claudin 3, claudin 4, claudin 7 and E-cadherin. Claudin-low tumors identified with this immunohistochemical panel, were associated with young age of onset, higher tumor grade, larger tumor size, extensive lymphocytic infiltrate and a circumscribed tumor margin. Patients with claudin-low tumors had a worse overall survival when compared to patients with luminal A type breast cancer. Interestingly, claudin-low tumors were associated with a low local recurrence rate following breast conserving therapy. In conclusion, a limited panel of antibodies can facilitate the identification of claudin-low tumors. Furthermore, claudin-low tumors identified in this manner display similar clinical, pathologic and survival characteristics to claudin-low tumors identified from fresh frozen tumor material using gene expression profiling.

MeSH terms

  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Cell Line, Tumor
  • Claudin-1 / genetics
  • Claudin-1 / metabolism*
  • Cluster Analysis
  • Cohort Studies
  • Female
  • Gene Expression Profiling*
  • Gene Expression Regulation
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Immunohistochemistry
  • Kaplan-Meier Estimate
  • Neoplasm Invasiveness
  • Neoplasm Recurrence, Local
  • Phenobarbital / metabolism
  • Phenotype
  • Prognosis
  • Treatment Outcome

Substances

  • CLDN1 protein, human
  • Claudin-1
  • Phenobarbital

Grants and funding

This work was supported by the Canadian Breast Cancer Foundation (http://www.cbcf.org/ontario/ApplyForGrants/Pages/default.aspx) to ALB, and by the Canadian Institutes of Health Research, grant no. MOP-142353 to JH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.