Loss of CSMD1 disrupts mammary epithelial morphogenesis

Introduction

CUB and Sushi multiple domain protein 1 (CSMD1) is a candidate tumour suppressor gene of unknown function. CSMD1 maps to chromosome 8p23, a region deleted in 50% of breast cancers (BC). We have examined the contribution of CSMD1 to the tumorigenic phenotype of mammary acini and evaluated its prognostic value in BC patients.

Materials and methods

A shRNA CSMD1 MCF10A three-dimensional matrigel model was established. Moreover, functional assays were performed using shCSMD1 cell lines. CSMD1 was tested by immunohistochemistry in 275 BC samples.

Results

Loss of CSMD1 in the MCF10A three-dimensional model resulted in an increased number of acini (P = 0.001), which are also larger in size (40%, P = 0.02) and misshapen relative to the control. Although expressing a high level of active caspase 3, shCSMD1 acini failed to form lumen.

Loss of CSMD1 expression caused a 56% (P = 0.001) increase in proliferation and a 44% (P = 0.0006) decrease in adhesion. shCSMD1 cells migrate much faster than control cells and showed 33% (P < 0.001) increase in invasion. These results were confirmed in two other cell lines.

Loss of CSMD1 expression was identified in 79/275 (28.7%) of BC cases, which was associated with high tumour grade (P = 0.003) and low overall survival (HR = 0.607, 95% CI = 0.4 to 0.91, P = 0.018). Moreover, CSMD1 is an independent predictor of overall survival (HR = 0.607, 95% CI = 0.4 to 0.91, P = 0.018) [1].

Conclusions

Loss of CSMD1 affects cell adhesion, proliferation, migration and invasion, which lead to disruption of mammary duct formation. Loss of CSMD1 is associated with poor prognosis in BC, suggesting its use as a new prognostic biomarker.