Abstract 350: Claudin 1 expression in the basal-like breast cancer subtype (BLBC) is age related and higher in postmenopausal women

Abstract

Abstract The claudins are a family of tight junction (TJ) proteins that are crucial for the organization of epithelial cell polarity, contribute to the transepithelial barrier that controls the transport of ions and small molecules and the overall maintenance of the differentiated state of epithelial cells. An absence of, or defects in tight junctions have been associated with development of the neoplastic phenotype. Claudin 1, a member of this family forms the backbone of the TJ strand and is primarily responsible for the regulation of the paracellular pathway function in epithelial cells. However, the role of claudin 1 in breast cancer is not known, but studies from our laboratory and others suggest that it may be that of a tumor suppressor. Paradoxically, our laboratory has also shown that claudin 1 protein expression is significantly higher in a particular subset of breast cancers, the basal-like subtype, an aggressive form of breast cancer associated with poor prognosis. To begin to delineate a direct functional role for claudin 1 in basal-like breast cancer (BLBC), we generated in vitro, a stably transfected shRNA claudin 1 knockdown model, using the basal-like BT20 human breast cancer (HBC) cell line which over-expresses endogenous claudin 1. As well, we over-expressed claudin 1 in another basal-like HBC cell line, MDA-MB231, which expresses low levels of endogenous claudin 1. Claudin 1 gene knockdown/over-expression was confirmed by western blot analysis. Cell cultures were then evaluated for changes in proliferation and migration. The differential expression of genes associated with epithelial-mesenchymal transition in the claudin 1 gene knockdown/over-expression clones was also investigated by qPCR using PCR arrays. Several significantly differentially expressed genes, such as BMP7, PAI1and SPP1 were identified. Additionally, to examine the clinical relevance of high claudin 1 in the basal-like human invasive breast cancers, we generated a BLBC tissue microarray and interrogated the association of high claudin 1 expression and patient survival and disease recurrence. In our cohort we found no correlation with claudin 1 expression with either of these parameters, but a significant association with age (p=0.0022). High claudin 1 expression was significantly associated with BLBC from postmenopausal women > 55 years of age. The heterogeneous nature of the disease presentation of breast cancer and the limitations in identifying clinically relevant subsets of patients are major challenges for current breast cancer diagnostic and therapeutic strategies. These studies will provide information which would further define this subset of breast cancer that is particularly difficult to treat. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 350. doi:1538-7445.AM2012-350