At the Cutting Edge
Is TP53 dysfunction required for BRCA1-associated carcinogenesis?

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Abstract

The identification of the breast/ovarian susceptibility genes, BRCA1 and BRCA2 was an important advancement in the field of breast and ovarian cancer research. About 40-50% of site specific hereditary breast cancers and up to 80% of hereditary breast-ovarian cancers result from mutations in the BRCA1 gene. Although BRCA1 mediates multiple functions in the cell, including a role in DNA damage repair and gene transcription, the role of BRCA1 has not completely been elucidated yet. It has been suggested that mutational inactivation of TP53 may be required for BRCA1-associated tumorigenesis. Several studies have shown that TP53 is more frequently inactivated in BRCA1-associated tumors than in sporadic breast or ovarian cancer. Up to 90% of BRCA1-associated tumors harbor either a TP53 mutation and/or TP53 protein accumulation. The remaining tumors may well have other alterations affecting the cell cycle checkpoint. Loss of this checkpoint may be obligatory for BRCA1-tumorigenesis. In this review, we discuss recent advances in BRCA1-research and stress the pivotal role TP53 may play in 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

References (102)

  • J.M. Schildkraut et al.

    Loss of heterozygosity on chromosome 17q11–21 in cancers of women who have both breast and ovarian cancer

    Am. J. Obstet. Gynecol.

    (1995)
  • B. Schlichtholz et al.

    p53 Mutations in BRCA1-associated familial breast cancer

    Lancet

    (1998)
  • R. Scully et al.

    Dynamic changes of BRCA1 subnuclear location and phosphorylation state are initiated by DNA damage

    Cell

    (1997)
  • R. Scully et al.

    Association of BRCA1 with Rad51 in mitotic and meiotic cells

    Cell

    (1997)
  • A. Shinohara et al.

    Rad51 protein involved in repair and recombination in S. cerevisiae is a RecA-like protein

    Cell

    (1992)
  • M. Shiohara et al.

    Absence of WAF1 mutations in a variety of human malignancies

    Blood

    (1994)
  • M.M. Tanner et al.

    Genetic aberrations in hypodiploid breast cancer: frequent loss of chromosome 4 and amplification of cyclin D1 oncogene

    Am. J. Pathol.

    (1998)
  • L.C. Verhoog et al.

    Survival and tumour characteristics of breast-cancer patients with germline mutations of BRCA1

    Lancet

    (1998)
  • A.K.C. Wong et al.

    RAD51 interacts with the evolutionary conserved BRC motifs in the human breast cancer susceptibility gene brca2

    J. Biol. Chem.

    (1997)
  • S.F. Anderson et al.

    BRCA1 protein is linked to RNA polymerase II holoenzyme complex via RNA helicase A

    Nat. Genet.

    (1998)
  • A. Berchuck et al.

    Frequency of germline and somatic BRCA1 mutations in ovarian cancer

    Clin. Cancer Res.

    (1998)
  • P. Bork et al.

    A superfamily of conserved domains in DNA damage-responsive cell cycle checkpoint proteins

    FASEB

    (1997)
  • J. Brugarolas et al.

    Double indemnity: p53, BRCA and cancer

    Nat. Med.

    (1997)
  • S. Buchhop et al.

    Interaction of p53 with the human Rad51 protein

    Nucleic Acids Res.

    (1997)
  • Y.L. Chai et al.

    The second BRCT domain of BRCA1 proteins interact with p53 and stimulates transcription from the p21WAF1/CIP1 promoter

    Oncogene

    (1999)
  • M.S. Chapman et al.

    Transcriptional activation by BRCA1

    Nature

    (1996)
  • Y. Chen et al.

    BRCA1 is a 220-kDa nuclear phosphoprotein that is expressed and phosphorylated in a cell cycle dependent manner

    Cancer Res.

    (1996)
  • R.S. Cornelis et al.

    High allele loss rates at 17q12–q21 in breast and ovarian tumors from BRCA1-linked families. The Breast Cancer Linkage Consortium

    Genes Chromosomes Cancer

    (1995)
  • T. Crook et al.

    p53 mutation with frequent novel codons but not a mutator phenotype in BRCA1- and BRCA2-associated breast tumours

    Oncogene

    (1998)
  • C.S. Cropp et al.

    Identification of three regions on chromosome 17q in primary human breast carcinomas which are frequently deleted

    Cancer Res.

    (1993)
  • J.Q. Cui et al.

    BRCA1 splice variants BRCA1a and BRCA1b associate with CBP co-activator

    Oncol. Rep.

    (1998)
  • A. Dobrovic et al.

    Methylation of the BRCA1 gene in sporadic breast cancer

    Cancer Res.

    (1997)
  • C. Dudenhoffer et al.

    Specific mismatch recognition in heteroduplex intermediates by p53 suggests a role in fidelity control of homologous recombination

    Mol. Cell. Biol.

    (1998)
  • D.F. Easton et al.

    Breast and ovarian cancer incidence in BRCA1-mutation carriers. Breast Cancer Linkage Consortium

    Am. J. Hum. Genet.

    (1995)
  • F. Eisinger et al.

    Germ line mutation at BRCA1 affects the histoprognostic grade in hereditary breast cancer

    Cancer Res.

    (1996)
  • S. Fan et al.

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

    Oncogene

    (1998)
  • W.D. Foulkes et al.

    Very frequent loss of heterozygosity throughout chromosome 17 in sporadic ovarian carcinoma

    Int. J. Cancer

    (1993)
  • W.D. Foulkes et al.

    Germ-line BRCA1 mutation is an adverse prognostic factor in Ashkenazi Jewish women with breast cancer

    Clin. Cancer Res.

    (1997)
  • P.A. Futreal et al.

    BRCA1 mutation in primary breast and ovarian carcinomas

    Science

    (1994)
  • S.A. Gayther et al.

    Germline mutations of the BRCA1 gene in breast and ovarian cancer families provide evidence for a genotype–phenotype correlation

    Nat. Genet.

    (1995)
  • O.K. Glebov et al.

    Frequent p53 gene mutations and novel alleles in familial breast cancer

    Cancer Res.

    (1994)
  • L.C. Gowen et al.

    Brca1 deficiency results in early embryonic lethality characterized by neuroepithelial abnormalities

    Nat. Genet.

    (1996)
  • L.C. Gowen et al.

    BRCA1 is required for transcription-coupled repair of oxidative DNA damage

    Science

    (1998)
  • J.M. Gudas et al.

    Hormone-dependent regulation of BRCA1 in human breast cancer cells

    Cancer Res.

    (1995)
  • J.M. Gudas et al.

    Cell cycle regulation of BRCA1 messenger RNA in human breast epithelial cells

    Cell Growth Differ.

    (1996)
  • R. Hakem et al.

    Partial rescue of Brca15–6 early embryonic lethality by p53 or p21 null mutation

    Nat. Genet.

    (1997)
  • J.T. Holt et al.

    Growth retardation and tumour inhibition by BRCA1

    Nat. Genet.

    (1996)
  • L. Hosking et al.

    A somatic BRCA1 mutation in an ovarian tumour

    Nat. Genet.

    (1995)
  • S.P. Hussain et al.

    Molecular epidemiology of human cancer: Contribution of mutation spectra studies of tumor suppressor genes

    Cancer Res.

    (1998)
  • R.A. Jensen et al.

    BRCA1 is secreted and exhibits properties of a granin

    Nat. Genet.

    (1996)
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