Aberrant expression of tumor suppressors CADM1 and 4.1B in invasive lesions of primary breast cancer
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The tumor suppressor genes CADM1/TSLC1 and DAL-1/4.1B are frequently inactivated by promoter methylation in non-small cell lung cancer. The proteins they encode, CADM1 and 4.1B, form a complex in human epithelial cells and are involved in cell–cell adhesion.
Expression of CADM1 and 4.1B proteins was examined by immunohistochemistry in 67 primary breast cancer and adjacent noncancerous tissues. CADM1 and 4.1B messenger RNA (mRNA) was detected by reverse-transcription polymerase chain reaction (RT-PCR). The methylation status of the CADM1 and 4.1B promoters was determined quantitatively by bisulfite treatment followed by pyrosequencing.
CADM1 and 4.1B protein signals were detected along the cell membrane in normal mammary epithelia. By contrast, 47 (70%) and 49 (73%) of 67 primary breast cancers showed aberrant CADM1 and 4.1B staining, respectively. Aberrant CADM1 staining was more frequently observed in pT2 and pT3 tumors and for stages II and III (P = 0.045 and P = 0.020, respectively), while aberrant 4.1B staining was more often observed in tumors with lymph node metastasis, for pT2 and pT3 tumors, and for stages II and III (P = 0.0058, P = 0.0098, and P = 0.0007, respectively). Furthermore, aberrant CADM1 and 4.1B expression was preferentially observed in invasive relative to noninvasive lesions from the same specimen (P = 0.036 and P = 0.0009, respectively). Finally, hypermethylation of CADM1 and 4.1B genes was detected in 46% and 42% of primary breast cancers, respectively.
Our findings suggest that aberrant CADM1 and 4.1B expression is involved in progression of breast cancer, especially in invasion into the stroma and metastasis.
KeywordsCADM1 4.1B Tumor suppressor protein Breast cancer Methylation
We thank Dr. H. Miura, Dr. K. Nakai, Dr. K. Senuma, Dr. I. Abe, Dr. T. Kosaka, Dr. H. Shimizu, and all members of the Breast and Endocrine Surgery Department at Juntendo University for collecting breast cancer samples. We also thank Dr. Y. Tsuboi and Dr. M. Nagata for fruitful discussion and Ms. Seiko Iwata and Ms. Takako Kohmoto for secretarial assistance. This work was supported by a Grant-in-Aid for Scientific Research (B) [22300336 to Y.M.]; a Grant-in-Aid for Young Scientists (B) [22700914 to M.I. and 21790309 to M.S.-Y.] from the Ministry of Education, Culture, Sports, Science, and Technology, Japan; and a Grant-in-Aid for the Third-Term Comprehensive Control Research for Cancer from the Ministry of Health, Labor, and Welfare, Japan (Y.M.).
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