At the Cutting EdgeIs TP53 dysfunction required for BRCA1-associated carcinogenesis?
Introduction
Since its identification in 1994, the human breast and ovarian cancer susceptibility gene (BRCA1) on chromosome 17q21 (Miki et al., 1994) has proven to be a gene of great interest. Inherited mutations in the BRCA1 gene predispose women to breast and ovarian cancer and account for nearly half of familial breast cancers and for up to 80% of families with both breast and ovarian cancer (Easton et al., 1995). In addition, germ-line mutations of the BRCA1 gene confer a substantially increased risk for prostate cancer in male probands (Ford et al., 1994). Moreover, a role for BRCA1 as a potential human prostate tumor suppressor has been proposed (Fan et al., 1998).
Carriers of a BRCA1 germ-line mutation have a 90% life-time risk to develop either breast or ovarian cancer (Easton et al., 1995) although certain BRCA1 mutations have been associated with a considerable lower penetrance (Struewing et al., 1997). Compared to non-familial (sporadic) breast and ovarian cancer, BRCA1-associated tumors occur at younger age, are more frequently bilateral, are of higher histological grade, show an increased proliferative capacity (as demonstrated by higher S-phase fractions and higher mitotic index) and are more often aneuploid (Jacquemier et al., 1995, Eisinger et al., 1996, Marcus et al., 1996, Verhoog et al., 1998). Interestingly, the total number of chromosomal gains and losses, estimated by comparative genomic hybridization, has been found to be twice as high in BRCA1-linked breast cancers than in sporadic breast cancers (Tirkkonen et al., 1997). In contrast with sporadic breast cancer, tumors from BRCA1 germ-line carriers are more frequently estrogen receptor (ER), progesterone receptor (PgR) and HER2/neu negative (Johannsson et al., 1997, Verhoog et al., 1998) and demonstrate more TP53 alterations. The latter alterations are also more prevalent in BRCA1-associated tumors from ovarian cancer patients but alterations in the oncogenes K-RAS, ERBB-2 (HER2/neu), c-MYC and AKT2, all known to play a limited role in sporadic ovarian tumorigenesis, have not been reported (Rhei et al., 1998).
Whether the prognosis of BRCA1-related breast and ovarian cancer differs from their sporadic counterparts is still a matter of debate. The prognosis for women with BRCA1-related breast or ovarian cancer has been reported to be similar (Marcus et al., 1996, Johannsson et al., 1998, Robson et al., 1998, Wagner et al., 1998, Verhoog et al., 1998) or worse (Foulkes et al., 1997, Ansquer et al., 1998) than that for age-matched breast or ovarian cancer patients without BRCA1 mutations. In contrast with these studies, carriers with ovarian cancer have been reported to have a more favorable outcome than non-carriers (Rubin et al., 1996).
The majority (86%) of BRCA1 mutations that have been described are frameshift, nonsense or splice-site mutations that generate a truncated BRCA1 protein (Shattuck-Eidens et al., 1995). A genotype-phenotype correlation has been suggested by Gayther et al. (1995) who observed that mutations in the 3′ third of the gene are associated with a lower proportion of ovarian cancer. Furthermore, mutations in either the amino or the carboxyl termini are correlated with highly proliferating breast cancers (Sobol et al., 1996). Tumors from BRCA1-germ line carriers show loss of heterozygosity (LOH) around the BRCA1 locus at 17q21 which invariably involves loss of the wild-type allele (Smith et al., 1992, Neuhausen and Marshall, 1994, Cornelis et al., 1995, Merajver et al., 1995a, Schildkraut et al., 1995). This implies that BRCA1 may function as a tumor suppressor gene. The tumor suppressive function of BRCA1 is further supported by experimental studies which show that antisense oligonucleotides accelerate the growth of normal and malignant mammary epithelial cell lines (Thompson et al., 1995). Moreover, introduction of the wild-type BRCA1 gene inhibits growth of breast and ovarian cancer cell lines (Holt et al., 1996). Interestingly, loss of heterozygosity at the BRCA1 locus also frequently occurs in sporadic breast (Cropp et al., 1993, Saito et al., 1993, Futreal et al., 1994, Nagai et al., 1994) and ovarian carcinomas (Foulkes et al., 1993, Futreal et al., 1994, Takahashi et al., 1995, Saretzki et al., 1997). However, somatic BRCA1 mutations are rarely observed in these tumors (Futreal et al., 1994, Hosking et al., 1995, Merajver et al., 1995b, Berchuck et al., 1998). The reduction in BRCA1 mRNA levels observed in invasive breast tumors relative to the normal breast epithelium and carcinoma in situ suggests a role for BRCA1 in sporadic breast cancer (Thompson et al., 1995). The reduced BRCA1 levels in these tumors may result from alterations other than coding-region mutations including LOH or deletion, preferential alellic expression (Özçelik et al., 1998) or hypermethylation of the promoter region (Dobrovic and Simpfendorfer, 1997, Rice et al., 1998).
Both hereditary and sporadic cancer are thought to arise from an accumulation of gene defects. In addition to the germ line inheritance of a mutant BRCA1 allele, not only the wild-type BRCA1 allele has to be inactivated but other acquired somatic alterations must be involved in the development of a BRCA1-associated tumor as well. Recent studies suggest that the TP53 gene is a key factor in BRCA1-associated carcinogenesis. Besides an overview of BRCA1, this paper will focus on the proposed prominent role of TP53 in BRCA1-associated carcinogenesis.
Section snippets
BRCA1 structure and function
The BRCA1 gene consists of 24 exons, spanning a 100 kb region on chromosomal band 17q21. The gene encodes a 1863 amino acid nuclear protein which is expressed in a variety of adult human tissues including breast, ovary, testis and thymus (Miki et al., 1994). BRCA1 expression is relatively high in tissues undergoing rapid growth and differentiation and has been shown to be regulated by the steroid hormones estrogen and progesterone (Gudas et al., 1995, Marquis et al., 1995). The induction of
TP53 alterations in BRCA1-associated tumors
Although the previous section predicts an almost all-important role of TP53 in BRCA1-associated tumorigenesis and BRCA1-associated tumors might be expected to exhibit loss of TP53 function, the final proof of which role TP53 really plays in BRCA1-associated tumorigenesis must come from tumors. In early studies, before the discovery of the BRCA1 gene, immunohistochemically detected TP53 protein accumulation was seen more often in tumors from patients with familial breast (34%) or familial breast
Is TP53 dysfunction required for BRCA1-associated tumorigenesis?
Although the inheritance of a BRCA1 germ-line mutation subsequently followed by loss of the wild-type allele are initiating events in the development of a BRCA1-associated tumor, additional somatic mutations in oncogenes and tumor suppressor genes are required. Data from mouse models suggest that loss of TP53 function may be a critical event in BRCA1-related pathogenesis. Indeed, the data summarized in Section 3 demonstrate that there is an indisputable increase in the frequency of TP53
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2022, Leukemia ResearchCitation Excerpt :One patient had a germline BRCA1 mutation and a history of high-grade serous carcinoma of the ovaries and had TP53 R175H in exon 5. Notably, patients with germline BRCA1/2 mutation commonly harbor somatic TP53 mutation in the tumors [25–27]. The other patient was HIV positive, had a history of HHV8-positive diffuse large B-cell lymphoma and had TP53 R248W mutation in exon 7.
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2022, Seminars in Cancer BiologyIndividual factors define the overall effects of dietary genistein exposure on breast cancer patients
2019, Nutrition ResearchCitation Excerpt :DNA damage repair dysfunction produced by TP53 mutations leads to abnormal cell proliferation and subsequent carcinogenesis, and these mutations are often detected in breast cancer patients [126,127]. It is reported that at least 90% of BRCA1-mutated breast tumors carry TP53 dysfunctions [128]. Currently, the drug resistance caused by TP53 mutations is the most discussed issue [129]; however, some results indicate that breast tumors with TP53 mutations might exhibit higher sensitivity to radiotherapy and chemotherapy [130].
PARP inhibitors for BRCA1/2 mutation-associated and BRCA-like malignancies
2014, Annals of OncologyCitation Excerpt :TCGA [4] describes molecular similarities between HGSOC and triple-negative breast cancers (TNBCs), including dysregulation of the p53 and Rb checkpoints, leading to alterations in the expression of cell proliferation genes, DNA synthesis, DNA damage repair, cell cycle regulation, and apoptosis. p53 mutations are found in nearly 90% of HGSOC and in 80% of TNBC, both cancers with BRCA1/2 loss-of-function cohorts [3, 4, 15]. Chromosome breaks caused by loss of BRCA1/2 function activate p53-dependent checkpoint controls and/or apoptosis to prevent tumor formation.