BRCA1 as a potential human prostate tumor suppressor: modulation of proliferation, damage responses and expression of cell regulatory proteins

Oncogene. 1998 Jun 11;16(23):3069-82. doi: 10.1038/sj.onc.1202116.


In addition to breast and ovarian cancer in women, recent evidence suggests that germ-line mutations of the breast cancer susceptibility gene-1 (BRCA1) also confer an increased life-time risk for prostate cancer in male probands. However, it is not known if and how BRCA1 functions in prostate cancer. We stably expressed wild-type (wt) and tumor-associated mutant BRCA1 transgenes in DU-145, a human prostate cancer cell line with low endogenous expression of BRCA1. As compared with parental cells and vector transfected clones, wtBRCA1 clones exhibited: (1) a slightly decreased proliferation rate (doubling time = 25 h as compared with 22 h for control cells); (2) a (3-6)-fold increase in sensitivity to chemotherapy drugs (adriamycin, camptothecin, and taxol); (3) increased susceptibility to drug-induced apoptosis; (4) reduced repair of single-strand DNA strand breaks; and (5) alterations in expression of key cellular regulatory proteins (including BRCA2, p300, Mdm-2, p21(WAF1/CIP1), Bcl-2 and Bax). Clones transfected with the 5677insA breast cancer-associated mutant BRCA1 (insBRCA1) displayed a similar phenotype to wtBRCA1 clones, except that insBRCA1 clones had a significantly decreased proliferation rate (doubling time = 42 h). On the other hand, cells transfected with with 185delAG mutant BRCA1 showed no obvious phenotype as compared with parental or vector transfected cells. These findings suggest that BRCA1 may function as a human prostate tumor suppressor by virtue of its ability to modulate proliferation and various components of the cellular damage response. They also suggest several potential target gene products for a BRCA1 prostate tumor suppressor function.

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Apoptosis
  • BRCA1 Protein / genetics
  • BRCA1 Protein / physiology*
  • Cell Cycle
  • Cell Division
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins / biosynthesis
  • DNA Damage
  • Doxorubicin / pharmacology
  • Female
  • Gene Expression
  • Genes, Tumor Suppressor*
  • Humans
  • Male
  • Mutagenesis
  • Nuclear Proteins / biosynthesis
  • Prostatic Neoplasms / genetics*
  • Proto-Oncogene Proteins / biosynthesis
  • Proto-Oncogene Proteins c-bcl-2 / biosynthesis
  • Proto-Oncogene Proteins c-mdm2
  • Trans-Activators*
  • Transcription Factors / biosynthesis
  • Transfection
  • Tumor Cells, Cultured


  • Antineoplastic Agents
  • BRCA1 Protein
  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Trans-Activators
  • Transcription Factors
  • Doxorubicin
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2