Cables1 is a tumor suppressor gene that regulates intestinal tumor progression in ApcMin mice

The transformation of colonic mucosal epithelium to adenocarcinoma requires progressive oncogene activation and tumor suppressor gene inactivation. Loss of chromosome 18q is common in colon cancer but not in precancerous adenomas. A few candidate tumor suppressor genes have been identified in this region, including CABLES1 at 18q11.2-12.1. This study investigates the role of CABLES1 in an in vivo mouse model of intestinal adenocarcinoma and in human colon cancer cell culture. Apc(Min/+) mice were crossed with mice harboring targeted inactivation of the Cables1 gene (Cables1(-/-)). The intestinal tumor burden and tumor expression of -catenin and PCNA was compared in Cables1(+/+)Apc(Min/+) and Cables1(-/-)Apc(Min/+) mice. -catenin activity in human colon cancer cells with CABLES1 inactivation and intestinal progenitor cell function in Cables1(-/-) mice were assayed in vitro. The mean number of small intestinal tumors per mouse was 3.1 +/- 0.6 in Cables1(+/+) Apc(Min/+) mice, compared with 32.4 +/- 3.5 in the Cables1(-/-)Apc(Min/+) mice (P < 0.0001). Fewer colonic tumors were observed in Cables1(+/+)Apc(Min/+) mice (mean 0.6 +/- 0.1) compared with the Cables1(-/-)Apc(Min/+) mice (mean 1.3 +/- 0.3, P = 0.01). Tumors from Cables1(-/-)Apc(Min/+) mice demonstrated increased nuclear expression of -catenin and an increased number of PCNA-positive cells. In vitro studies revealed that CABLES1 deficiency increased -catenin dependent transcription and increased intestinal progenitor cell activity. Loss of Cables1 enhances tumor progression in the Apc(Min/+) mouse model and activates the Wnt/-catenin signaling pathway. Cables1 is a tumor suppressor gene on chromosome 18q in this in vivo mouse model and likely has a similar role in human colon cancer.