Leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) is a pan-ErbB negative regulator and intestinal stem cell marker down-regulated in many
malignancies. We previously reported that 14 of 16 Lrig1-CreERT2/CreERT2 (Lrig1(-/-)) mice developed duodenal
adenomas, providing the first in vivo evidence that Lrig1 acts as a
tumor suppressor. We extended this study to a larger cohort and found that 49 of 54 Lrig1(-/-) mice develop duodenal
adenomas beginning at 3 months. Most
adenomas were histologically low grade and overlaid expanded Brunner glands. There was morphologic and biochemical blurring of the boundary between the epithelium and Brunner glands with glandular coexpression of ErbB2, which is normally restricted to the epithelium, and the Brunner gland marker Mucin6. Some
adenomas were high grade with reduced Brunner glands. At age 4 to 5 weeks, before
adenoma formation, we observed enhanced proliferation in Brunner glands and, at 2 months, an increase in the size of the Brunner gland compartment. Elevated expression of the
epidermal growth factor receptor (Egfr)
ligands amphiregulin and β-cellulin, as well as Egfr and phosphorylated Egfr, was detected in
adenomas compared with adjacent normal tissue. These
adenomas expressed the gastric-specific genes gastrokine1 and mucin5ac, indicating gastric
metaplasia. Moreover, we found that a subset of human duodenal
tumors exhibited features of LRIG1(-/-)
adenomas, including loss of LRIG1, gastric
metaplasia (MUCIN5AC and MUCIN6), and increased
amphiregulin and Egfr activity.