DNA methylation of RASSF1A, HIN-1, RAR-beta, Cyclin D2 and Twist in in situ and invasive lobular breast carcinoma

Int J Cancer. 2003 Dec 20;107(6):970-5. doi: 10.1002/ijc.11508.


Little is known about epigenetic silencing of genes by promoter hypermethylation in lobular breast cancers. The promoter methylation status of 5 cancer-related genes (RASSF1A, HIN-1, RAR-beta, Cyclin D2 and Twist) was evaluated in 2 types of lobular cancers, in situ (LCIS) and invasive lobular carcinomas (ILC) (n = 32), and compared to ductal in situ (DCIS) and invasive (IDC) breast cancers (n = 71). By using methylation-specific PCR (MSP), 100% of ILC and 69% of LCIS cases were found to have 1 or more hypermethylated genes among the panel of 5 genes (compared to 100% IDC and 95% of DCIS). Two or more hypermethylated genes were detected per tumor in 79% of invasive and 61% of in situ lobular carcinomas compared to 81% of IDC and 77% of DCIS. By contrast, DNA from nearly all normal reduction mammoplasty tissues (n = 8) was unmethylated for the 5 genes. The methylation profiles of lobular vs. ductal carcinomas with respect to RASSF1A, Cyclin D2, RARbeta, and Hin-1 genes were similar, suggesting that gene silencing by promoter hypermethylation is likely to be important in both groups of diseases. Distinctly different, Twist was hyper- methylated less often in ILC (16%, 3/19 cases) than in IDC (56%, 15/27 cases) (p = 0.01). These results suggest that these 2 types of tumors share many common methylation patterns and some molecular differences. Additional studies might lend further understanding into the etiology and clinical behavior of this tumor type.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Base Sequence
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Carcinoma, Ductal / genetics
  • Carcinoma, Ductal / pathology
  • Carcinoma, Lobular / genetics*
  • Carcinoma, Lobular / pathology
  • Cyclin D2
  • Cyclins / genetics*
  • Cytokines / genetics*
  • DNA Methylation*
  • DNA Primers
  • Female
  • Genes, Tumor Suppressor
  • Humans
  • Middle Aged
  • Multigene Family
  • Neoplasm Invasiveness
  • Neoplasm Proteins / genetics*
  • Nuclear Proteins*
  • Receptors, Retinoic Acid / genetics*
  • Reference Values
  • Transcription Factors / genetics*
  • Tumor Suppressor Proteins*
  • Twist-Related Protein 1


  • CCND2 protein, human
  • Cyclin D2
  • Cyclins
  • Cytokines
  • DNA Primers
  • Neoplasm Proteins
  • Nuclear Proteins
  • RASSF1 protein, human
  • Receptors, Retinoic Acid
  • SCGB3A1 protein, human
  • TWIST1 protein, human
  • Transcription Factors
  • Tumor Suppressor Proteins
  • Twist-Related Protein 1
  • retinoic acid receptor beta