Ovarian Cancer Gene Therapy with BRCA1—An Overview

  • Patrice S. Obermiller
  • Jeffrey T. Holt
Part of the Methods in Molecular Medicine™ book series (MIMM, volume 35)

Abstract

The human breast and ovarian cancer susceptibility gene BRCA1 is a tumorsuppressor gene which is mutated and lost in hereditary breast and ovarian cancer, and has both alleles mutated in approximately 10-15% of cases of sporadic ovarian cancer. Studies of chromosome loss in ovarian cancer show that at least one allele of the BRCA1 gene is lost or mutated in up to 70% of sporadic ovarian cancers. Although no sporadic breast cancers contain BRCA1 mutations, our published study shows that expression of the mRNA is decreased suggesting that the BRCA1 gene is altered quantitatively in sporadic cancer and qualitatively in hereditary cancer. Decreased expression of the BRCA1 gene may also be important in cases of sporadic ovarian cancer that do not have BRCA1 mutations. The majority of mutant alleles are nonsense and should produce truncated proteins, which are predicted to vary in length from 5% to 99% of full-length protein. A relatively small number of missense mutations have also been identified, most commonly in the predicted ring finger domain in the N-terminus. Patients with mutations in BRCA1 differ clinically from nonfamilial breast cancer because the breast cancer is earlier in onset and more highly associated with ovarian cancer. We have recently obtained data indicating that families with BRCA1 mutations in the 3′ portion of the gene develop early-onset breast cancer, but do not develop ovarian cancer, suggesting that expression of a truncated BRCA1 protein may suppress ovarian tumors, but not breast tumors (1).

Keywords

Toxicity Catheter Leukemia Creatinine Assure 

References

  1. 1.
    Holt, J. T., Thompson, M. E., Szabo, C., Robinson-Benion, C., Arteaga, C. L., King, M-C., and Jensen, R. A. (1996) Growth retardation and tumor inhibition by BRCA1. Nature Genet. 12, 298–302.PubMedCrossRefGoogle Scholar
  2. 2.
    Steeg, P. (1996) Granin expectations in breast cancer? Nature Genet. 12, 223–225.PubMedCrossRefGoogle Scholar
  3. 3.
    Jensen, R. A., Thompson, M. E., Szabo, C., Jetton, T., van der Meer, R., Helou, B., et al. (1996) BRCA1 is secreted and exhibits properties of a granin. Nature Genet. 12, 303–308.PubMedCrossRefGoogle Scholar
  4. 4.
    Holt, J. T., et al. (1998) Growth retardation and tumor inhibition by BRCA1 (correction). Nature Genet. 19, 102.Google Scholar
  5. 5.
    Arteaga, C. L. and Holt, J. T. (1996) Tissue-targeted antisense anti-fos retroviral vector inhibits established breast cancer xenografts in nude mice. Cancer Res. 56, 1098–1103.PubMedGoogle Scholar
  6. 6.
    Thompson, M. E., Jensen, R. A., Obermiller, P. S., Page, D. L., and Holt, J. T. (1995) Decreased expression of BRCA1 accelerates growth and is frequently present during sporadic breast cancer progression. Nature Genet. 9, 444–450.PubMedCrossRefGoogle Scholar
  7. 7.
    Obermiller, P. S., Pilaro, A. M., Arteaga, C. L., and Holt, J. T. (1997) Inflammation alters distribution of antifos retroviral vector after murine intracavitary delivery, in Clinical Trials of Genetic Therapy with Antisense DNA and DNA Vectors (Wickstrom, E., ed.), Marcel Dekker, New York.Google Scholar
  8. 8.
    Tait, D. L., Obermiler, P. S., Redlin-Frazier, S., Jensen, R. A., Welcsh, P., Dann, J., et al. (1997) Phase I trial of BRCA1 retroviral gene therapy for ovarian cancer. Clin. Cancer Res. 3, 1959–1968.PubMedGoogle Scholar

Copyright information

© Humana Press Inc. 2000

Authors and Affiliations

  • Patrice S. Obermiller
    • 1
  • Jeffrey T. Holt
    • 1
  1. 1.Department of Cell BiologyVanderbilt UniversityNashville

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