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PubMed1999

Is TP53 dysfunction required for BRCA1-associated carcinogenesis?

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.

BRCA2 Protein↗
PubMed1997

Retinoblastoma protein expression and radiation response in muscle-invasive bladder cancer.

PURPOSE: The retinoblastoma protein (pRB) is a key regulator of the G1 cell cycle checkpoint and has been implicated as having a role in G1 arrest and apoptosis induced by radiation damage. In this report we examine the association between pRB expression and radiation response in patients treated between 1960 and 1983 with preoperative radiotherapy (50 Gy in 25 fractions) followed 4-6 weeks later by radical cystectomy. The correlation of pRB to patient outcome and how this relationship is complimentary to that seen with p53 staining status is also described. METHODS AND MATERIALS: Immunohistochemical staining of pRB and p53 in paraffin-embedded tumor sections using WL-1 anti-RB and DO1 anti-p53 antibodies was considered adequate in 98 and 97 pretreatment tumor samples, respectively. There were 46 patients with clinical Stage T2, 28 with Stage T3a, and 24 with Stage T3b disease. The median age was 62 years and follow-up for those living was 85 months. RESULTS: Staining for pRB was negative in 30% of the cases. Correlations were observed between pRB negativity and high pretreatment apoptosis level (p = 0.06), locally advanced clinical stage (p = 0.01), increased clinical-to-pathologic downstaging (p = 0.014), and more pathologic complete responses (Path-CRs; p = 0.019). Several other factors were tested and were not associated with pRB status, including p53 expression. RB status was the only pretreatment prognostic factor in the univariate analyses that correlated with downstaging and was independently associated with Path-CR using multivariate logistic regression. Despite these significant relationships, no correlations with patient outcome were observed when the entire cohort was analyzed. Restriction of the analyses to Stage T3b patients, however, revealed that pRB negativity predicted for enhanced distant metastasis freedom (p = 0.006, log rank) and overall survival (p = 0.02). The overexpression of p53 also correlated with distant metastasis freedom and overall survival in Stage T3b patients. Patient outcome was best when RB negative and p53 negative staining were seen. CONCLUSION: Our results indicate that loss of RB function as measured by immunohistochemical staining is the strongest correlate of radiation response thus far recognized. Loss of RB expression also predicted for poor outcome in Stage T3b patients, which appeared to compliment the finding of normal p53 expression. While normal RB protein expression is usually associated with better patient outcome, other series have not examined patients treated with radiotherapy. The absence of pRB may be a useful marker for selecting patients for bladder preservation with radiotherapy, particularly when wild-type p53 is present.

Adult↗
PubMed1996

The cellular and molecular pathogenesis of colorectal cancer.

The development of colorectal neoplasia originates from normal colonic mucosa, progresses to the adenomatous polyp, and later may evolve into carcinoma. This procession of histologic change can be defined by a series of successive waves of clonal expansion that contain certain genetic alterations. These genetic alterations include mutations in the K-ras oncogene and mutation in the one allele coupled with loss of the second allele for the tumor suppressor genes APC, DCC, and p53. The normal forms of these genes encode for proteins that regulate cell growth, cell-to-cell adhesion, and cell cycle checkpoints. Information on the function of these genes, as well as a proposed model of sequential mutation and loss of these regulatory genes during colorectal tumorigenesis are presented.

Adenomatous Polyposis Coli↗
PubMed2001

Repair of DNA interstrand cross-links.

DNA interstrand cross-links (ICLs) are very toxic to dividing cells, because they induce mutations, chromosomal rearrangements and cell death. Inducers of ICLs are important drugs in cancer treatment. We discuss the main properties of several classes of ICL agents and the types of damage they induce. The current insights in ICL repair in bacteria, yeast and mammalian cells are reviewed. An intriguing aspect of ICLs is that a number of multi-step DNA repair pathways including nucleotide excision repair, homologous recombination and post-replication/translesion repair all impinge on their repair. Furthermore, the breast cancer-associated proteins Brca1 and Brca2, the Fanconi anemia-associated FANC proteins, and cell cycle checkpoint proteins are involved in regulating the cellular response to ICLs. We depict several models that describe possible pathways for the repair or replicational bypass of ICLs.

Animals↗
PubMed1997

A developmental timer that regulates apoptosis at the onset of gastrulation.

Recent work identified an apoptotic program in gastrulation stage Xenopus embryos (Anderson, J.A., Lewellyn, A.L., Maller, J.L., 1997. Mol. Biol. Cell 8, 1195-1206; Stack, J.H., Newport, J.W., 1997. Development 124, 3185-3195). Here, we characterize in detail this maternal cell death program, which is set up at fertilization and abruptly activated at the onset of gastrulation, following DNA damage or treatment of embryos with inhibitors of transcription, translation, or replication, between the time of fertilization and the midblastula transition (MBT). This apoptotic pathway is activated under tightly regulated developmental control(s): if the same treatments are applied after the MBT the apoptotic response is abrogated. Embryos displayed many characteristic apoptotic features, including DNA fragmentation, caspase activation, and embryonic death was blocked in vivo by the ectopic expression of Bcl-2, or injection of the caspase-3 inhibitor z-DEVD-fmk. The precise timing and the execution of this maternal cell death program is set at fertilization and does not depend on the type of stress applied, on cell cycle progression, or on de novo protein synthesis. This maternal developmental program might palliate the lack of cell cycle checkpoints in the pre-MBT embryo.

Animals↗
PubMed1996

Phosphatidylinositol 3-kinase related kinases.

Studies in yeast, files and mammalian cells have uncovered a novel family of signal-transducing kinases which bear an evolutionary relationship to phosphatidylinositol 3-kinase. These phosphatidylinositol 3-kinase related enzymes play critical roles in DNA repair, V(D)J recombination and cell-cycle checkpoints, and their dysfunction leads to clinical manifestations ranging from immunodeficiency to cancer.

Amino Acid Sequence↗
PubMed1999

Chromosomal breakage syndromes.

Immune deficiency and chromosome fragility are hallmarks of two human diseases, ataxia telangiectasia and Nijmegen breakage syndrome. The genes mutated in these diseases, ATM and NBS1, have been cloned and there has been considerable recent progress on deciphering the function of the protein products implicated in these disorders and how their absence in the disease states relates to the immunodeficiency and chromosome fragility observed. The function of the two protein products, Atm and Nibrin, in effecting DNA repair and cell cycle checkpoints in response to genomic insult provides a framework for understanding the cellular response to DNA damage.

Ataxia Telangiectasia↗
PubMed1998

Cellular responses to DNA damage.

The exposure of cells to DNA damage inducers triggers a wide range of cellular responses including an alteration in gene expression, a delay in cell-cycle progression and the stimulation of DNA repair. In multicellular organisms, DNA damage can also activate programmed cell death. Recently, several signaling pathways that link DNA damage to gene expression and to the cell-cycle checkpoints have been identified. These pathways establish a framework for future studies of DNA damage responses.

Animals↗
PubMed1996

Keeping the centrosome cycle on track. Genome stability.

The protein kinase Mps1 and p53 both function in centrosome duplication and the spindle cell-cycle checkpoint. Defects in these functions can be potent sources of genomic instability by allowing mitosis to proceed with aberrant mitotic spindles.

Animals↗
PubMed1996

Synergistic interactions between XPC and p53 mutations in double-mutant mice: neural tube abnormalities and accelerated UV radiation-induced skin cancer.

The significance of DNA repair to human health has been well documented by studies on xeroderma pigmentosum (XP) patients, who suffer a dramatically increased risk of cancer in sun-exposed areas of their skin [1,2]. This autosomal recessive disorder has been directly associated with a defect in nucleotide excision-repair (NER) [1,2]. Like human XP individuals, mice carrying homozygous mutations in XP genes manifest a predisposition to skin carcinogenesis following exposure to ultraviolet (UV) radiation [3-5]. Recent studies have suggested that, in addition to roles in apoptosis [6] and cell-cycle checkpoint control [7] in response to DNA damage, p53 protein may modulate NER [8]. Mutations in the p53 gene have been observed in 50% of all human tumors [9] and have been implicated in both the early [10] and late [11] stages of skin cancer. To examine the consequences of a combined deficiency of the XPC and the p53 proteins in mice, we generated double-mutant animals. We document a spectrum of neural tube defects in XPC p53 mutant embryos. Additionally, we show that, following exposure to UV-B radiation, XPC p53 mutant mice have more severe solar keratosis and suffer accelerated skin cancer compared with XPC mutant mice that are wild-type with respect to p53.

Animals↗
PubMed2001

Promotion of Dnl4-catalyzed DNA end-joining by the Rad50/Mre11/Xrs2 and Hdf1/Hdf2 complexes.

S. cerevisiae RAD50, MRE11, and XRS2 genes are required for telomere maintenance, cell cycle checkpoint signaling, meiotic recombination, and the efficient repair of DNA double-strand breaks (DSB)s by homologous recombination and nonhomologous end-joining (NHEJ). Here, we demonstrate that the complex formed by Rad50, Mre11, and Xrs2 proteins promotes intermolecular DNA joining by DNA ligase IV (Dnl4) and its associated protein Lif1. Our results show that the Rad50/Mre11/Xrs2 complex juxtaposes linear DNA molecules via their ends to form oligomers and interacts directly with Dnl4/Lif1. We also demonstrate that Rad50/Mre11/Xrs2-mediated intermolecular DNA joining is further stimulated by Hdf1/Hdf2, the yeast homolog of the mammalian Ku70/Ku80 heterodimer. These studies reveal specific functional interplay among the Hdf1/Hdf2, Rad50/Mre11/Xrs2, and Dnl4/Lif1 complexes in NHEJ.

Catalysis↗
PubMed2004

Total synthesis of ustiloxin D and considerations on the origin of selectivity of the asymmetric allylic alkylation.

As part of investigations into cell cycle checkpoint inhibitors, an asymmetric synthesis of the antimitotic natural product, ustiloxin D, has been completed. A salen-Al-catalyzed aldol reaction was employed to construct a chiral oxazoline 9 (99% yield, 98% ee) that served the dual purpose of installing the necessary 1,2-amino alcohol functionality as well as providing an efficient synthon for the requisite methylamino group at C9. The chiral aryl-alkyl ether was assembled using a Pd-catalyzed asymmetric allylic alkylation that notably delivered a product with stereochemistry opposite to that predicted by precedent. The linear tetrapeptide was subsequently cyclized to produce ustiloxin D. The mechanistic origin of the allylic alkylation selectivity was further investigated, and a working hypothesis for the origin of the observed stereoselectivity has been proposed.

Alkylation↗
PubMed2001

The role of c-erbB-2/HER2/neu in breast cancer progression and metastasis.

Gene amplification and/or overexpression of the c-erbB-2/HER2/neu tyrosine kinase are linked with poor prognosis in breast cancer. This is manifest in shorter disease-free intervals, increased risk of metastasis, and resistance to many types of therapy. The molecular mechanisms and signaling circuitry underlying these phenomena are now being elucidated. c-erbB-2, although having no known soluble ligand, is transactivated by heterodimerization with other family members (EGFR, c-erbB-3, c-erbB-4). Receptor activation potentiates tumor cell motility, protease secretion and invasion, and also modulates cell cycle checkpoint function, DNA repair, and apoptotic responses. Since it is expressed at low levels in normal adult tissues, c-erbB-2 is an ideal target for therapy. There is reason for optimism that agents targeting c-erbB-2 signaling will have profound and selective effects in breast cancer, either as single agents or more likely in combination with other therapeutic agents, to enhance their potency.

Breast Neoplasms↗
PubMed2002

Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations.

Mutations in BRCA1 and BRCA2 confer a high risk of breast and ovarian cancer, but account for only a small fraction of breast cancer susceptibility. To find additional genes conferring susceptibility to breast cancer, we analyzed CHEK2 (also known as CHK2), which encodes a cell-cycle checkpoint kinase that is implicated in DNA repair processes involving BRCA1 and p53 (refs 3,4,5). We show that CHEK2(*)1100delC, a truncating variant that abrogates the kinase activity, has a frequency of 1.1% in healthy individuals. However, this variant is present in 5.1% of individuals with breast cancer from 718 families that do not carry mutations in BRCA1 or BRCA2 (P = 0.00000003), including 13.5% of individuals from families with male breast cancer (P = 0.00015). We estimate that the CHEK2(*)1100delC variant results in an approximately twofold increase of breast cancer risk in women and a tenfold increase of risk in men. By contrast, the variant confers no increased cancer risk in carriers of BRCA1 or BRCA2 mutations. This suggests that the biological mechanisms underlying the elevated risk of breast cancer in CHEK2 mutation carriers are already subverted in carriers of BRCA1 or BRCA2 mutations, which is consistent with participation of the encoded proteins in the same pathway.

Breast Neoplasms↗
PubMed2003

The Fanconi anaemia/BRCA pathway.

Fanconi anaemia (FA) is a rare genetic cancer-susceptibility syndrome that is characterized by congenital abnormalities, bone-marrow failure and cellular sensitivity to DNA crosslinking agents. Seven FA-associated genes have recently been cloned, and their products were found to interact with well-known DNA-damage-response proteins, including BRCA1, ATM and NBS1. The FA proteins could therefore be involved in the cell-cycle checkpoint and DNA-repair pathways. Recent studies implicate the FA proteins in the process of repairing chromosome defects that occur during homologous recombination, and disruption of the FA genes results in chromosome instability--a common feature of many human cancers.

Animals↗
PubMed2006

Germline CHEK2 mutations and colorectal cancer risk: different effects of a missense and truncating mutations?

Germline mutations in cell cycle checkpoint kinase 2 (CHEK2) have been associated with a range of cancer types, in particular of the breast and prostate. Protein-truncating mutations in CHEK2 have been reported to confer higher risks of cancer of the breast and the prostate than the missense I157T variant. In order to estimate the risks of colorectal cancer associated with truncating and missense CHEK2 mutations, we genotyped 1085 unselected colorectal cancer cases and 5496 controls for four CHEK2 founder mutations present in Poland. We observed an increased risk of colorectal cancer in association with the missense I157T mutation (odds ratios (OR) = 1.5; 95% CI 1.2-2.0; P = 0.002) but not with truncating mutations (OR = 1.0; 95% CI 0.5-1.8; P = 0.9); however the difference in the two OR was not statistically significant (P = 0.2). We conclude that the I157T mutation increases the risk of colorectal cancer in the population, but that truncating mutations may confer a lower risk or no increase in risk. It is important that other studies of CHEK2 mutation carriers be conducted to confirm this hypothesis.

Adult↗
PubMed2000

Retinoblastoma susceptibility protein, Rb, possesses multiple BRCT-Ws, BRCA1 carboxyl-terminus-related W regions with DNA break-binding activity.

The BRCT region, the carboxyl-terminus of BRCA1 (the breast cancer susceptibility gene 1 product), is ubiquitous in several proteins that participate in cell cycle checkpoints and DNA repair. We have previously shown that the BRCT regions of TopBP1 (DNA topoisomerase II binding protein 1) and BRCA1 bound DNA breaks. A BRCT-related region, BRCT-W1, in the retinoblastoma susceptibility gene product (Rb) also could bind DNA fragments, independently of DNA sequences. Five BRCT-W regions were found in the Rb family. All BRCT-Ws of Rb bound DNA fragments. Electron microscopy and treatment with an exonuclease showed that BRCT-Ws bound double-strand DNA breaks. Since some BRCTs are exceptional common relating elements in tumor suppression, our findings reveal novel aspects of the tumor suppression mechanism.

Amino Acid Sequence↗
PubMed2000

Small molecule inhibitors of dual specificity protein phosphatases.

One hallmark of neoplasia is the deregulation of cell cycle control mechanisms, which is secondary to altered protein phosphorylation. Dual specificity protein phosphatases uniquely dephosphorylate both phosphoserines/threonines and phosphotyrosines on the same protein substrate. As a class they regulate intracellular signaling through the mitogen activated and stress activated kinases and govern cellular movement through G1/S and G2/M cell cycle checkpoints by affecting the activity of cyclin-dependent kinases. In particular, the Cdc25 phosphatases, which dephosphorylate cyclin-dependent kinases, are overexpressed in many human tumors and this increased expression is associated with a poor prognosis. In addition to expression levels, the intracellular activity of Cdc25 phosphatases is determined by their subcellular distribution and physical proximity to substrates. Small molecules that either inhibit the catalytic activity or alter the subcellular distribution of these dual specificity protein phosphatases could provide effective tools to interrogate the role of phosphorylation pathways and may afford new approaches to the management of cancer.

Animals↗