Decrease in Expression of BRMS1 Correlates with the Tumor Progression and Metastatic Potential of Colorectal Adenocarcinoma
PA Phadke, H Ashby-Richardson, A Shepard Barry, SP Naber, DR Welch. Tufts Medical Center, Boston, MA; University of Alabama at Birmingham, Birmingham, AL
Background: Breast Cancer Metastasis Suppressor 1 (BRMS1), a recently discovered metastasis suppressor gene, has been found to suppress multiple organ metastasis by affecting numerous steps of the metastatic cascade, without affecting primary tumor growth. Studies using human tissue have demonstrated decreased BRMS1 levels in malignant melanoma and breast cancer. However, the expression pattern of BRMS1 in primary and metastatic colorectal carcinoma has not been tested. The current study, the first of its kind, explores BRMS1 expression patterns in matched normal colonic tissue, primary colorectal carcinomas, and lymph node metastasis to explore its role in human colorectal carcinoma progression and metastasis.
Design: A tissue array containing 25 cases of primary colorectal carcinoma (19 colon and 6 rectal) with matched lymph node metastasis (22 cases) and adjacent normal colonic mucosa was utilized for the study. Immunohistochemical staining for BRMS1 was performed using a custom made monoclonal antibody (Clone 3a1.21) on paraffin-embedded formalin-fixed tissue. Expression was graded based on intensity (0-5) in the cells staining for BRMS1.
Results: BRMS1 staining was predominantly nuclear, with a diffuse and intense staining pattern. The normal adjacent colonic mucosa showed the highest score (3.9 0.22), while both the primary and metastatic adenocarcinomas showed a significant decrease in BRMS1 expression compared to normal mucosa (P<0.001). While the metastases had the lowest mean score (2.5 0.25), there was no statistical difference between primary and metastatic adenocarcinoma. Additionally, no difference in BRMS1 expression was noted between grade 1, 2, and 3 primary adenocarcinomas.
Conclusions: A dramatic reduction in BRMS1 expression in primary and metastatic colorectal adenocarcinomas as compared to normal adjacent mucosa suggests a critical role for the BRMS1 protein in the regulation of tumor progression and metastasis. Additionally, the lack of a significant difference in expression profile among different grades of primary tumor suggests that BRMS1 may have a role early in the tumor progression cascade. Currently, studies using survival data are underway to address the prognostic and potential therapeutic utility of BRMS1 in advanced and metastatic colorectal carcinoma.
Monday, March 9, 2009 1:00 PM
Poster Session II # 78, Monday Afternoon