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Japanese Journal of Clinical Oncology 32:79-84 (2002)
© 2002 Foundation for Promotion of Cancer Research

Promoter Hypermethylation and Post-transcriptional Mechanisms for Reduced BRCA1 Immunoreactivity in Sporadic Human Breast Cancers

Kazuaki Miyamoto1,2, Takashi Fukutomi3, Kiyoshi Asada1, Kuniko Wakazono1, Hitoshi Tsuda4, Toshimasa Asahara2, Takashi Sugimura1 and Toshikazu Ushijima1,+,§

1Carcinogenesis and 4Pathology Division, National Cancer Center Research Institute, Tokyo, 2Second Department of Surgery, Hiroshima University School of Medicine, Hiroshima and 3Department of Surgery, National Cancer Center Hospital, Tokyo, Japan

Background: Germline mutation of BRCA1 is well known to cause familial breast cancer. Although somatic mutations of the BRCA1 gene are rare in sporadic breast cancers, a high incidence of reduced BRCA1 immunoreactivity has been demonstrated. As one of the mechanisms for this, gene silencing by hypermethylation of the BRCA1 promoter region has been reported. Here, we show the presence of a post-transcriptional mechanism by examining promoter hypermethylation, mRNA expression levels and immunoreactivity of BRCA1 in sporadic human breast cancers

Methods: Paired samples of 20 invasive ductal carcinomas and one invasive lobular carcinoma were obtained from sporadic breast cancer cases. The BRCA1 protein expression levels were determined by immunohistochemistry using a well-characterized antibody. The methylation status of the BRCA1 promoter region was determined by sequencing after bisulfite modification. The mRNA expression levels were determined by semi-quantitative reverse transcription polymerase chain reaction (PCR). Mutations in the entire BRCA1 coding region were analyzed by PCR single-strand conformation polymorphism analysis.

Results: Reduced immunoreactivity was observed in 13 of the 21 cancers. Hypermethylation was observed in five of the 13 cancers with reduced immunoreactivity and mRNA expression was almost absent in these five cancers. In the remaining eight cancers, mRNA expression was not decreased. None of the 21 cancers examined harbored BRCA1 mutations.

Conclusion: These findings showed that post-transcriptional mechanisms, such as low efficiency of translation or reduced stability of BRCA1 protein, are also involved in reduced BRCA1 immunoreactivity in sporadic breast cancers.

+ For reprints and all correspondence: Toshikazu Ushijima, Carcinogenesis Division, National Cancer Center Research Institute, 1–1 Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan. E-mail: tushijim@ncc.go.jp

§ Abbreviations: RT-PCR, reverse transcription polymerase chain reaction; SSCP, single-strand conformation polymorphism; LOH, loss of heterozygosity; IDC, invasive ductal carcinoma; ILC, invasive lobular carcinoma


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