The functional analysis of the tumour suppressor gene CSMD1

Cub Sushi Multiple Domains 1 (CSMD1) is a novel tumour suppressor gene, which encodes a 388KDa protein with a putative tyrosine phosphorylation site. CSMD1 has been shown to be deleted in various cancers including breast cancer, with CSMD1 deletions generating more mesenchymal phenotypes in cells. Due to these facts it is therefore vital to understand the mechanisms behind CSMD1 action. To analyse this two unique studies were undertaken; one in vivo examining the development of the mouse mammary gland and one in vitro exploring the effect of CSMD1 knockdown on cancer cell development in U2-OS and T47D cells. The in vivo study explored the effect Csmd1 knockout has during pubertal development in the mammary gland. The analysis revealed a role for CSMD1 in the early stages of pubertal development. The Csmd1 knockout mice exhibited larger mammary gland growth, increased ductal area and terminal end bud number by 6 weeks of age. These mice also showed varied protein expression patterns compared to the wild type mice, with alterations in proteins such as Fak, Stat1, PR and Akt. The in vitro study identified a highly unique role for CSMD1 in U2-OS cells and a role in T47D cells. The T47D with CSMD1 knockdown appeared to promote a more mesenchymal phenotype, whereas the U2-OS cells with CSMD1 knockdown expressed a more epithelial phenotype. This analysis also highlighted roles for CSMD1 in the regulation of proteins such as STAT1 and FAK. When combining the 2 data sets there are strong connections between CSMD1 and EMT regulation, which would explain the rapid growth observed in the mice and the changes overserved in the cell lines. From the protein analysis strong links between CSMD1 and, FAK and STAT1 expression have been identified, leading to potential roles for CSMD1 in cell adhesion and in immune evasion respectively.