Claudin-2 is an independent negative prognostic factor in breast cancer and specifically predicts early liver recurrences

Mol Oncol. 2014 Feb;8(1):119-28. doi: 10.1016/j.molonc.2013.10.002. Epub 2013 Oct 14.


Background: Predicting any future metastatic site of early-stage breast cancer is important as it significantly influences the prognosis of advanced disease. This study aimed at investigating the potential of claudin-2, over-expressed in breast cancer liver metastases, as a biomarker for predicting liver metastatic propensity in primary breast cancer.

Methods: Claudin-2 expression was analyzed in two independent cohorts. Cohort 1 included 304 women with metastatic breast cancer diagnosed between 2002 and 2007, while cohort 2 included 237 premenopausal women with early-stage node-negative breast cancer diagnosed between 1991 and 1994. Global transcriptional profiling of fine-needle aspirates from metastases was performed, followed by immunohistochemical analyses in archival primary tumor tissue. Associations between claudin-2 expression and relapse site were assessed by univariable and multivariable Cox regression models including conventional prognostic factors. Two-sided statistical tests were used.

Results: CLDN2 was significantly up-regulated (P < 0.001) in liver metastases compared to other metastatic sites. Claudin-2 protein was more frequently expressed in primary tumors from patients who subsequently developed liver metastases (P = 0.02) and high expression was associated with a shorter metastasis-free interval (cohort 1, HR = 1.4, 95% CI = 1.0-1.9; cohort 2, HR = 2.2, 95% CI = 1.3-3.5). Specifically, a significantly shorter interval between primary tumor diagnosis and liver-specific recurrence was observed among patients with high levels of claudin-2 expression in the primary tumor (cohort 1, HR = 2.3, 95% CI = 1.3-3.9).

Conclusion: These results suggest a novel role for claudin-2 as a prognostic biomarker with the ability to predict not only the likelihood of a breast cancer recurrence, but more interestingly, the liver metastatic potential of the primary tumor.

Keywords: BCSS; Breast cancer; CI; CLDN2; Claudin-2; ER; HR; IHC; LNM; LiMFS; Liver metastasis; OR; PR; Prognostic biomarker; RFS; TMA; breast cancer specific survival; claudin-2 mRNA; confidence interval; estrogen receptor; hazard ratio; immunohistochemistry; liver metastasis-free survival; lymph node metastasis; odds ratio; progesterone receptor; relapse-free survival; tissue microarray.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast / metabolism
  • Breast / pathology*
  • Breast Neoplasms / diagnosis
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology*
  • Claudin-2 / analysis*
  • Claudin-2 / genetics
  • Cohort Studies
  • Female
  • Humans
  • Liver / metabolism
  • Liver / pathology
  • Liver Neoplasms / diagnosis
  • Liver Neoplasms / genetics
  • Liver Neoplasms / pathology
  • Liver Neoplasms / secondary*
  • Middle Aged
  • Neoplasm Recurrence, Local / diagnosis
  • Neoplasm Recurrence, Local / genetics
  • Neoplasm Recurrence, Local / pathology
  • Neoplasm Recurrence, Local / secondary*
  • Prognosis
  • Transcriptome
  • Up-Regulation*


  • Claudin-2