Stayce E. Beck

BMP suppresses PTEN expression via RAS/ERK signaling

Bone morphogenetic protein (BMP), a member of the transforming growth factor β family, classically utilizes the SMAD signaling pathway for its growth suppressive effects, and loss of this signaling cascade may accelerate cell growth. In the colon cancer predisposition syndrome Juvenile Polyposis, as well as in the late progression stages of non-syndromic colorectal cancers, SMAD4 function is typically abrogated. Here, we utilized the SMAD4-null SW480 colon cancer cell line to examine BMPs effect on a potential target gene, PTEN, and how its expression might be regulated. Initial treatment of the SMAD4-null cells with BMP resulted in mild growth suppression, but with prolonged exposure to BMP, the cells become growth stimulatory, which coincided with observed decreases in transcription and translation of PTEN, and with corresponding increases in phospho-AKT protein levels. BMP-induced PTEN suppression was mediated via the RAS/ERK pathway, as pharmacologic inhibition of RAS/ERK, or interference with protein function in the cytosol by DN-RAS prevented BMP-induced growth promotion and changes in PTEN levels, as did treatment with noggin, a BMP ligand inhibitor. Thus, BMP downregulates PTEN via RAS/ERK in a SMAD4-null environment that contributes to cell growth, and constitutes a SMAD4-independent but BMP-responsive signaling pathway.

Evidence for an hMSH3 defect in familial hamartomatous polyps

Patients with hamartomatous polyposis syndromes have increased risk for colorectal cancer (CRC). Although progression of polyps to carcinoma is observed, pathogenic mechanisms remain unknown. The authors examined whether familial hamartomatous polyps harbor defects in DNA mismatch repair (MMR), and assayed for somatic mutation of PTEN, a gene inactivated in the germline of some hamartomatous polyposis syndrome patients.

Cyclooxygenase-2 expression in polyps from a patient with juvenile polyposis syndrome with mutant BMPR1A

Objectives: Cyclooxygenase-2 (COX-2) expression is increased in colorectal cancers and has been reported to be upregulated in Peutz-Jeghers polyps. To determine whether germline and somatic loss of BMPR1A in polyps from a patient with juvenile polyposis syndrome have altered COX-2 expression, we characterized a patient with juvenile polyposis syndrome for BMPR1A germline mutations and examined the polyps for BMPR1A expression and COX-2 expression. Patients and Methods: DNA analysis for BMPR1A was performed on a patient with juvenile polyposis syndrome. Multiple polypectomies were performed, and several polyps showed adenomatous change. Genomic DNA was extracted from polyp material for loss of heterozygosity (LOH) analyses with microsatellite markers. Immunohistochemistry was performed on sections using antibodies for BMPR1A and COX-2. Results: The kindred possessed a germline BMPR1A missense mutation. In polyp domains containing cystic and adenomatous epithelium, no LOH was observed using markers near the BMPR1A locus. Immunostaining indicated decreased expression of phospho-SMAD1 (pSMAD1), functionally downstream of the mutant BMPR1A receptor in the cystic epithelium, with further reduction in adenomatous portions within the polyp. COX-2 protein, normally not expressed in the colon, was present and increased in polyp epithelium. Conclusions: Decreased expression of pSMAD1 in the cystic epithelium with further reduction in the adenomatous area, and increase in COX-2 expression within polyps from the BMPR1A heterozygote, suggest a potential mechanism for adenomatous pathogenesis in these hamartomatous polyps. This may imply that COX-2 inhibitors could be a means for chemoprevention in this syndrome.