The Association between Defective BRCA1 and Mutant p53 and Its Correlation with Pathologic Characteristics of Sporadic Breast Carcinoma- An Investigation of the Caretaker-Gatekeeper Relationship

Jyh-Cherng Yu ； Chung-Tai Yue ； Cheng-Wen Wu ； Chen-Yang Shen

《Journal of Genetics and Molecular Biology》 12卷1期 (2001/03) Pp. 35-49

https://doi.org/10.30047/JGMB.200103.0006

並列摘要

Recent progress in understanding the function of the breast cancer susceptibility genes, BRCA1 and BRCA2, has suggested that the proteins encoded by these two genes participate in DNA repair, and thus play a “caretaker” role during breast tumorigenesis. Although the inactivation of these caretakers lowers the threshold to subsequent genetic damage resulting in a predisposition to the development of cancer, it does not directly cause cancer. To form a tumor, defective caretakers require the inactivation of additional cell-growth-controlling genes (“ gatekeepers” ). Studies of familial breast cancer have supported the possibility of the caretaker-gatekeeper model, by demonstrating a higher frequency of p53 (gatekeeper) mutation in breast cancers from mutant BRCA (caretaker) carriers. However, whether this model is also valid in sporadic breast cancers remains unclear. The present study examined 78 sporadic breast cancer specimens for the coexistence of defective BRCA genes (detected by loss of heterozygosity, LOH, at the loci for BRCAI and BRCA2) and p53 mutation. Although BRCA2 LOH was not associated with p53 mutation status, a significantly higher frequency of LOH at BRCA1 intragenic markers was consistently found in tumors with mutant p53 (P＜0.0l). Furthermore, this increased LOH at BRCAI in relation to mutant p53 was more significant in older patients (＞45 years old) (P＜0.05), and was linked with poor tumor grade (differentiation) (P＜0.0l). When the individual grade indices were considered independently, significantly increased frequencies to exhibit a high mitotic count (implying rapid cell proliferation) or grade 3 nuclear pleomorphism (implying genomic instability) were found in cancers harboring defective genotypes of RRCA1 and p53. However, the relationship between defective BRCAI and/or p53 and mitotic count was not similar to that between BRCA1-p53 and nuclear pleomorphism. Whereas BRCA1 LOH and p53 mutation were individually and independently correlated to high mitotic count, the proportion of tumor with pleomorphic nuclei increased as the number of defective genotypes of BRCA1 and p53 increased. These observations provide support for a link between sporadic breast cancer tumorigenesis and the caretaker(BRCA1)-gatekeeper(p53) mechanisms, but suggest that BRCA1 may play a dual role, both as caretaker and gatekeeper, in the development of sporadic breast cancer.

並列關鍵字

BRCA1 ； defective BRCA1 ； p53 ； mutant p53 ； sporadic breast carcinoma ； caretaker-gatekeeper relationship