Validation of ITGB1BP1 as a novel transcriptional target of CD44-Promoted Breast Cancer Progression

Background: Breast cancer (BC) is one of the most common cancers worldwide, and metastasis is its worst aspect and the first cause of death. Metastasis is a multistep process, where invasion is a recurring event. The process of BC cell invasion involves, in general, three major factors including, cell adhesion molecules (CAM), proteinases, and growth factors. CD44, a family of CAM proteins and the hyaluronic acid (HA) cell surface receptor, acts as cell differentiation, cell migration/invasion, and apoptosis regulator. To better understand the molecular mechanisms that underpin CD44-promoted BC cell invasion, our previous microarray gene expression profiling, using “TET-OFF” BC CD44-inducible cell experimental model, identified ITGB1BP1 as a novel potential transcriptional target of CD44. Methods: to test this hypothesis, both in vitro BC cell model, as well as ex-vivo tissue microarray (TMA) slides, containing adjacent sections from breast tumors of 113 BC patients were examined for the expression of both CD44 and its potential target gene expression, ITGB1BP1, by immunohistochemistry (IHC). Results: in vitro results revealed that HA-activation and induction of CD44 increased significantly the expression of its target gene, ITGB1BP1. Furthermore, IHC analysis of TMAs showed that overall 90% of the samples exhibited high CD44-immunostaining in the membrane while its target ITGB1BP1 was mainly observed in the cytoplasm and occasionally in the membrane. More interestingly, the patterns of expression of CD44 and its target ITGB1BP1 showed a parallel increase in the majority of highly invasive/metastatic tumor tissues when compared to less invasive breast tumor tissues. Consclusion: the present study provides for the first time substantial evidence supporting our hypothesis that ITGB1BP1is a potential novel transcriptional target that underpin CD44-promoted BC tumor cell progression.