title: Aberrant expression of tumor suppressors CADM1 and 4.1B in invasive lesions of primary breast cancer.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Molecular Pathology, Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, 108-8639, Tokyo, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Miwako
authors.initials: M
authors.lastname: Iwai
authors.forename: Taketo
authors.initials: T
authors.lastname: Kawai
authors.forename: Atsushi
authors.initials: A
authors.lastname: Arakawa
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ito
authors.forename: Mika
authors.initials: M
authors.lastname: Sakurai-Yageta
authors.forename: Akihiko
authors.initials: A
authors.lastname: Ito
authors.forename: Akiteru
authors.initials: A
authors.lastname: Goto
authors.forename: Mitsue
authors.initials: M
authors.lastname: Saito
authors.forename: Fujio
authors.initials: F
authors.lastname: Kasumi
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Murakami
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D019175:DNA Methylation; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D011401:Promoter Regions, Genetic; D012016:Reference Values; D017154:Stromal Cells / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000235:genetics; D008840:Microfilament Proteins
chemical_list: D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D007136:Immunoglobulins; D008565:Membrane Proteins; D025521:Tumor Suppressor Proteins; C403514:CADM1 protein, human; C116887:EPB41L3 protein, human; D008840:Microfilament Proteins