1111

CHEK1

CHK1;checkpoint kinase 1;CHEK1;checkpoint kinase 1

CHK1 checkpoint homolog|Checkpoint, S. pombe, homolog of, 1|Chk1-S|cell cycle checkpoint kinase|checkpoint kinase-1|serine/threonine-protein kinase Chk1

11q24.2

protein-coding

The haploinsufficient tumor suppressor Chk1 is essential for embryonic cells, but the consequences of Chk1 loss in adult tissues are unknown. Using conditional Chk1 mice, we find that proliferating mammary cells lacking Chk1 undergo apoptosis leading to developmental defects. Conditional Chk1 heterozygosity increased the number of S phase cells and caused spontaneous DNA damage. Chk1+/- epithelia also exhibit a miscoordinated cell cycle in which S phase cells display an early mitotic phenotype. These cells maintain high levels of Cdc25A, which can promote inappropriate cell cycle transitions. Thus, Chk1 heterozygosity results in three distinct haploinsufficient phenotypes that can contribute to tumorigenesis: inappropriate S phase entry, accumulation of DNA damage during replication, and failure to restrain mitotic entry.

To understand the importance of frequent deletions at chromosome 11q24.1-24.2 region in breast carcinoma, alterations (deletion/methylation) of the candidate genes LOH11CR2A, ROBO3, ROBO4, HEPACAM, PIG8 and CHEK1 located in this region were analyzed in 106 breast carcinoma samples. Among these genes, LOH11CR2A showed highest frequency of deletion (56%), followed by PIG8 (35%), CHEK1 (31%) and ROBO3/ROBO4/HEPACAM loci (28%). Comparable frequency of promoter methylation (26-35%) was observed for LOH11CR2A, CHEK1 and PIG8. Overall alterations (deletion/methylation) of these genes were in the following order: LOH11CR2A (60%) > PIG8 (46%) > CHEK1 (41%) and showed significant association with each other. Breast carcinoma samples that were estrogen/progesterone receptor negative showed significantly high deletion and overall alterations than estrogen/progesterone receptor positive samples for LOH11CR2A, CHEK1 and PIG8. The methylation and overall alteration of LOH11CR2A were significantly associated with tumor stages in breast carcinoma. However, in early/late onset and estrogen/progesterone receptor positive/negative breast carcinoma, the overall alterations of LOH11CR2A, PIG8 and CHEK1 were differentially associated with advanced stages, tumor grade and lymph node metastasis. Alterations of PIG8 and CHEK1 were significantly associated with poor prognosis in patients with early age of onset of the disease indicating significant prognostic importance. Quantitative mRNA expression analysis detected reduced expression of the genes in the order LOH11CR2A > CHEK1 > PIG8. Immunohistochemical analysis showed reduced protein expression of PIG8 and CHEK1 that was concordant with their molecular alterations. Thus, our study suggests that LOH11CR2A, PIG8 and CHEK1 are candidate tumor suppressor genes associated with breast carcinoma and have significant clinical as well as prognostic importance.