Evidence for a tumour suppressive function of APRG1 in breast cancer

Abstract

Introduction. Deletion mapping studies have shown that genes in the region 3p21.3 are often deleted in epithelial malignancies. Although the regions deleted differ between individual cancers there appears to be a specificity for the type of malignancy produced. As a result this area of chromosome 3 is thought to contain multiple tumour suppressor genes. The present study concentrates on one gene in that region, APRG1. This gene codes for a protein, which has been implicated in cell membrane interactions. The aim was to determine using quantitative PCR whether the levels of this gene were negatively correlated with clinical outcome in breast cancer.

Methods. One hundred and twenty tumour tissues and 33 normal tissues were analyzed. Levels of transcription of APRG1 were determined using real-time quantitative PCR. APRG1 expression was normalized against CK19. Levels of expression were analyzed against staging, nodal involvement, grade, distant metastasis and survival over a 6 year follow up period.

Results. Levels of APRG1 mRNA were lower in malignant tissues. They fell further with increasing stage using the TNM classification This became statistically significant when TNM stages 3 and 4 were compared to TNM 1 (p = 0.0046, p = 0.04, t-test). They were lower in those with positive nodes although this did not reach statistical significance. There was a statistically significant reduction in APRG1 in grade 3 tumours cf. grade 1 (p = 0.0081). APRG1 expression was highly negatively correlated with progressive disease: alive with metastasis (p = 0.0069), local recurrence (p = 0.0055), died of breast cancer (p = 0.11), all progressive disease (p = 0.035).

Conclusion. This study shows a compelling trend for APRG1 transcription levels to be lower in malignant tissues and lower still in those patients who develop progressive disease. There was also a statistically significant difference in APRG1 levels between grade 3 and grade 1 tumours. These results are highly suggestive of APRG1 acting as a tumour suppressor gene.