Inhibition of breast and brain cancer cell growth by BCCIPα, an evolutionarily conserved nuclear protein that interacts with BRCA2

Abstract

BRCA2 is a tumor suppressor gene involved in mammary tumorigenesis. Although important functions have been assigned to a few conserved domains of BRCA2, little is known about the longest internal conserved domain encoded by exons 14–24. We identified a novel protein, designated BCCIPα, that interacts with part of the internal conserved region of human BRCA2. Human BCCIP represents a family of proteins that are evolutionarily conserved, and contain three distinct domains: an N-terminus acidic domain (NAD) of 30–60 amino acids, an internal conserved domain (ICD) of 180–220 amino acids, and a C-terminus variable domain (CVD) of 30–60 amino acids. The N-terminal half of the human BCCIP ICD shares moderate homology with regions of calmodulin and M-calpain, suggesting that BCCIP may also bind Ca. Human cells express both a longer, BCCIPα, and a shorter, BCCIPβ, form of the protein, which differ in their CVD. BCCIP is a nuclear protein highly expressed in testis. Although BCCIPβ expression is relatively consistent in cancer cells, the expression of BCCIPα varies in cancer cell lines. The BCCIPα gene is located at chromosome 10q25.3–26.2, a region frequently altered in brain and other cancers. Furthermore, expression of BCCIPα inhibits breast and brain cancer cell growth, but fails to inhibit HT1080 cells and a non-transformed human skin fibroblast. These results suggest that BCCIPα is an important cofactor for BRCA2 in tumor suppression.