Role of BRCA1 in cellular resistance to paclitaxel and ionizing radiation in an ovarian cancer cell line carrying a defective BRCA1.
BRCA1, the gene responsible for approximately half of all cases of hereditary breast cancer and almost all cases of combined hereditary breast and ovarian cancer, has been implicated in the maintenance of genomic stability through DNA repair. This function is mediated, at least in part, through two tandem BRCA1 C-terminal (BRCT) repeats. The role of BRCA1 in the development of ovarian cancer is poorly understood, partially owing to the lack of ovarian cancer cell lines with defective BRCA1. The purpose of this study was to further characterize an endometrioid ovarian cancer cell line, SNU-251, which was previously reported to carry a nonsense mutation (from G to A) at amino acid 1815 of BRCA1. In addition, we examined the role of BRCA1 in the cell cycle and in the responses to the chemotherapy drug paclitaxel and ionizing radiation. Loss of the C-terminal 49 amino acids due to this point mutation did not affect the expression of the truncated BRCA1 protein, but caused a loss of transcriptional activation of the endogenous p21(WAF1/CIP1) gene, and could not sustain arrest in the G(2)/M phase of the cell cycle. The BRCA1 mutation in SNU-251 cells inhibited BRCA1 subnuclear assembly for DNA-damage repair and increased cellular sensitivity to ionizing radiation and paclitaxel. This sensitivity was reversed by reintroduction of ectopic wild-type BRCA1. Our results suggest that the deletion of the C-terminal 49 amino acids of BRCA1 results in a loss of BRCA1 function in the SNU-251 cell line. BRCA1 helps to mediate the resistance to both radiation and paclitaxel. Therefore, SNU-251 may be a useful model for studying the molecular mechanism of BRCA1 in the resistance of ovarian cancer to ionizing radiation and chemotherapy treatment and in the development of hereditary human ovarian cancer.
Zhou
Chenyi
C
Department of Pathology, Division of Pathology and Laboratory Medicine, Unit 85, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4095, USA.
Smith
Janice L
JL
Liu
Jinsong
J
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D019313:BRCA1 Protein / Q000378:metabolism*; D002460:Cell Line; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D051059:PTEN Phosphohydrolase; D017239:Paclitaxel / Q000494:pharmacology*; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism; D011839:Radiation, Ionizing; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; D019313:BRCA1 Protein; D025521:Tumor Suppressor Proteins; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D017239:Paclitaxel