Analysis of tumor suppressor genes for breast cancer

• Project/Area Number: 10151252
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas (A)
• Allocation Type: Single-year Grants
• Research Institution: Japanese Foundation For Cancer Research
• Principal Investigator: MIKI Yoshio The Cancer Institute, Japanese Foundation for Cancer Research Dept. of Molecular Diagonosis, Chief, 癌研究所・遺伝子診断研究部, 部長 (10281594)
• Project Period (FY): 1999
• Project Status: Completed (Fiscal Year 2000)
• Budget Amount: ¥24,000,000 (Direct Cost: ¥24,000,000); Fiscal Year 1999: ¥12,000,000 (Direct Cost: ¥12,000,000); Fiscal Year 1998: ¥12,000,000 (Direct Cost: ¥12,000,000)
• Keywords: Hereditary breast cancer / BRCA1 / BRCA2 / Rad51 / BRAP1 / Two-hybrid method / 遺伝子乳癌 / 癌抑制遺伝子

Research Abstract

Mutations in the BRCA1 and BRCA2 genes are involved in approximately 60% of familial breast cancers and these results indicate the existence of the 3rd major gene responsible for hereditary breast cancers. The isolation of this gene is important for the genetic testing of hereditary breast cancer. The yeast two-hybrid system was used to isolate BRCA2-binding proteins. We showed that BRCA2 formed a complex with Rad51 and the pattern of northern blot analysis of the Rad51 genewas closely similar to that of the BRCA2 gene. It is therefore possible that alterations of the Rad51 gene may be involved in the development of hereditary breast cancers. To investigate this possibility, we screened Japanese patients with hereditary breast cancer for Rad51 mutations and found a single alteration in exon 6. This was determined to be present in the germline in two patients with bilateral breast cancer. In both patients, blood DNAs showed G-to-A transition of the second nucleotide of codon 150, which results in the substitution of glutamine for arginine. Since this alteration was not present in patients with breast or colon cancer examined, we assume that this missense alteration is likely to represent a disease-associated mutation. Another candidate of BRCA2-binding protein, designated BRAP1, is highly homologous to Amphiphysin and BIN1, that were reported to be associated with breast carcinogenesis. The exon-intron boundaries of this gene were determined, and screening for germline mutation in breast cancer families and for somatic mutation in primary breast cancers was performed. Although no mutation was found in families and primary cancers, the expression level of the BRAP1 gene was detected to be remarkably decreased in breast cancer cell lines and pancreas cancer cell lines.
We have described the possibility that a small portion of bilateral breast cancers is due to germline alterations of Rad51. However, the 3rd major breast cancer susceptibility gene remains unknown ; intense efforts will be required to isolate the gene (s) responsible.

Research Products

• [Publications] Katagiri,T., et al.: "Multiple possible sites of BRCA2 interactingwith DNA repair protein Rad51."Genes, Chromosomes & Cancer,. 21. 217-222 (1998)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Kuno,T., et al.: "Bilateral nonpalpable breast carcinomas in a patient with BRCA2 germ line mutation and past history of osteosarcoma."Breast Cancer,. 6. 51-54 (1999)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Noguchi,S., et. al.: "Clinicopathologic analysis of BRCA1- or BRCA2-associated hereditary breast carcinoma in Japanese women."Cancer. 85. 2200-2205 (1999)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Kato,M., et al.: "Identification of Rad51 alteration in patients with bilateral breast cancer."J Hum. Genet.. (in press).
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Yano,K., et al.: "Nuclear Locarization signals of the BRCA2 protein."Biochem Biophys Res Commun.. (in press).
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Katagiri, T., Saito, H., Shinohara, A., Ogawa, H., Kamada, N., Nakamura, Y., Miki, Y.: "Multiple possible sites of BRCA2 interactingwith DNA repair protein Rad51."Genes, Chromosomes & Cancer. 21. 217-222 (1998)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Kuno, T., Fukutomi, T., Akashi-Tanaka, S., Nanasuwa, T., Kanai, Y., Tsuda, H., Nomizu, T., and Miki, Y.: "Bilateral nonpalpable breast carcinomas in a patient with BRCA2 germ line mutation and past history of osteosarcoma."Breast Cancer. 6. 51-54 (1999)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Noguchi, S., Kasugai, T., Miki, Y., Fukutomi, T., Emi, M., Nomizu, T.: "Clinicopathologic analysis of BRCA1- or BRCA2-asociated hereditary breast carcinoma in Japanese women."Cancer. 85. 2200-2205 (1999)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Kato, M., Yano, K., Matsuo, F., Saito, H., Katagiri, T., Kurumizaka, H., Yoshimoto, M., Kasumi, F., Akiyama, F., Sakamoto, G., Nagawa, H., Nakamura, Y., Miki, Y.: "Identification of Rad51 alteration in patients with bilateral breast cancer."J Hum.Gener.. (in press.).
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Yano, K., Morotomi, K., Saito, H., Kato, M., Matsuo, F., Miki, Y.: "Nuclear Locarization signals of the BRCA2 protein."Biochem Biophys Res Commun. (in press).
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Katagiri, T., et al.: "Multiple possible sites of BRCA2 interactingwith DNA repair protein Rad51"Genes, Chromosomes & Cancer,. 21. 217-222 (1998)
• [Publications] Kuno, T., et al.: "Bilateral nonpalpable breast carcinomas in a patient with BRCA2 germ line mutation and past history of osteosarcoma"Breast Cancer,. 6. 51-54 (1999)
• [Publications] Noguchi, S., et al.: "Clinicopathologic analysis of BRCA1 - or BRCA2 - associated hereditary breast carcinoma in Japanese women"Cancer. 85. 2200-2205 (1999)
• [Publications] Kato, M., et al.: "Identification of RAD51 alteration in patients with bilateral breast cancer"J Hum. Genet.. (in press.).
• [Publications] Yano, K., et al.: "Nuclear Locarization signals of the BRCA2 protein"Biochem Biophys Res Commun.. (in press.).
• [Publications] Emi,M.: "Multiplex mutation screening of the BRCA1 gene in 1000 Japanese breast cancers." Jpn.J.Cancer Res.89. 12-16 (1998)
• [Publications] Katagiri,T.: "Multiple possible sites of BRCA2 interacting with DNA repair protein Rad51." Genes, Chromosomes & Cancer. 21. 217-222 (1998)
• [Publications] Katagiri,T.: "High proportion of missense mutations of the BRCA1 and BRCA2 gene in Japanese breast cancer families." J.Human Genet.43. 42-48 (1998)
• [Publications] Kuno,T.: "Bilateral nonpalpable breast carcinomas in a patient with BRCA2 germ line mutation and past history of osteosarcoma." Breast Cancer. 6. 51-54 (1999)