Oncogenes and Tumor Suppressor Genes
Cancer genetics: Tumor suppressor meets oncogene in cancer development, gene expression changes in cancer cells themselves have  describing a relationship between the adenomatous polyposis coli (APC) tumor. Saunders, ; Chapter 7: Oncogenes and Tumor Suppressor Genes pp. .. eration, and these safeguards must be overcome to develop cancer. Cell Cycle Control by Oncogenes and Tumor Suppressors: Driving the Rather than lacking function, cancer cells reproduce at a rate far beyond the normally .. suppressor genes, link cell cycle control to tumor formation and development.
Notably, a single nucleotide polymorphism within the first intron of Mdm2 has been shown to affect promoter strength and affect the level and activities of p53 subsequently Bond et al. Expression of hundreds of genes is directly regulated by p Centrosome amplification occurs frequently in cells harboring TP53 mutations, partly through overactivation of CDKs by cyclin E and cyclin A reviewed in Fukasawa This in turn results in chromosome instability, a hallmark of solid tumors.
Loss of p53 allows efficient reprogramming of somatic cells Kawamura et al. In mammary gland, loss of p53 result in aberrant asymmetric cell divisions of mammary stem cells Cicalese et al. These recent results continue to expand our understanding of the tumor suppressor mechanisms of p In this model, cancer stem cells undergo frequent symmetric cell division and expansion.
Reactivation of p53 by pharmacological intervention restores asymmetric cell division Cicalese et al. In a separate model, expression of the exonless TP53 allele in neural stem cells was followed by the expansion of transient-amplifying progenitor-like cells and subsequent development of malignant astrocytic glioma Wang et al.
These studies indicate a role of p53 in the regulation of stem cell division in addition to its well-documented role in transformation. The majority of cancer-associated mutations in TP53 are missense mutations of the DNA binding domain. Some mutations induce genetic instability by inactivating ATM reviewed in Xu Mouse models of missense mutations corresponding to those in human mutant TP53 reveal a gain-of-function.
Although mutant p53 levels are increased in most tumors, only low levels of mutant p53 are present in normal mouse tissues initially, which indicates additional events are needed to allow mutant p53 to escape MDM2-dependent degradation reviewed in Brosh and Rotter This complex is involved in both nonhomologous end joining and homologous recombinational repair. Mouse embryonic fibroblasts deficient in Brca1 have impaired homologous recombinational repair Moynahan et al.
This region binds to phospho-peptides Manke et al. Three BRCA1 protein complexes have been characterized. BRCA2 mutations have been linked to a wide spectrum of cancers. In contrast, BRCA1 mutation is primarily associated with breast and ovarian cancers. Developmental defects and early embryonic death have been observed in Brca1 homozygous knockout mice reviewed in Dasika et al.
Several further lines of evidence indicate that BRCA1 plays a role in mammary development and differentiation. Mouse mammary tissue harboring a conditional Brca1 knockout displays abnormal ductal morphogenesis Xu et al.
Importantly, the epithelial progenitor cell population is expanded in BRCA1 carriers. This highlights the haplo-insufficiency phenotype of BRCA1 in mammary epithelial differentiation Lim et al.
Thus, the effects of BRCA1 on mammary cell differentiation appear to be dosage-dependent Ginestier et al. BRCA2 carriers develop different subtypes of breast cancer. BRC repeats bind to the Rad51 recombinase Chen et al.
At the carboxyl terminus of BRCA2 is a region with extensive secondary structure that interacts with the evolutionarily conserved protein DSS1. Indeed, both the formation of Rad51 nuclear filaments and Radmediated strand exchange during homologous recombination are regulated by BRCA2 reviewed in Thorslund and West Brca2 homozygous knockout mice either die during embryogenesis or survive beyond birth, depending on the mutation Dasika et al.
Several conditional knockout models of these two tumor suppressor genes have been established see the following. Because of differential splicing, the exon less Brca1 isoform is also present in wild-type mice and the protein product is located in the nucleus—like the full-length Brca1 Huber et al. All other alleles are predicted to produce aberrant protein products. Different mutant TP53 alleles, including null and internally truncated alleles, are generated, which can result in different phenotype.
Indeed, mutant but not null mutation promotes expansion of neuronal progenitor cells and subsequent astrocytic glioma formation Wang et al. Cre transgenes under the control of various different promoters have been used for the conditional inactivation of Brca1.
Thus, these models differ in the nature of mutation as well as cell types expressing mutant alleles. Mammary tumors developed in these mice at low frequency after the 10—13 months of latency.
Rediscovering Biology - Online Textbook: Unit 8 Cell Biology & Cancer
Introduction of heterozygous p53 mutation significantly shortened tumor latency Brodie et al. This model indicates that exon less Brca1 isoform is deficient in tumor suppression. Within exon 11, a unique ATM phosphorylation site exists. Mice homozygous for the phosphorylation mutant show aging phenotype and have elevated irradiation-induced tumorigenesis Kim et al.
Because expression of this Cre transgene does not require pregnancy, the interaction between tumor suppressor genes and ovarian hormones can be addressed. In contrast to wild-type and pdeficient mammary epithelial cells, proliferation of Brca1- and pdeficient mammary epithelial cells was uniquely sensitive to progesterone. Furthermore, progesterone receptors were stabilized in these cells.
Antiprogesterone treatment in pubertal mice prevented or delayed mammary tumorigenesis Poole et al. These mice develop mammary tumors with full penetrancy and a median tumor latency of 6. In line with recent reports Atchley et al. These findings raise the possibility that the cells of origin in BRCA1-mediated breast carcinogenesis may be heterogeneous.
The Brca1 and p53 mutations and the cell type s targeted differ in each of the above models. Together, the findings from these models and recent studies of BRCA1-associated breast cancer indicate that tumor cells can arise from multiple cell types in the mammary gland. The KCre transgenic approach, however, restricts deletion of Brca2 exon 11 and p53 exons to the skin, myoepithelial and luminal epithelial cells in the mammary gland, and some other tissues Jonkers et al.
Mammary and skin tumors developed at high frequencies in these mice Jonkers et al. Surprisingly, invasive adenocarcinomas that are histologically uniform developed in these mice, in contrast to the different breast cancer subtypes seen in BRCA2 carriers, in which loss of heterozygosity leads to tumorigenesis.
Mammary adenocarcinomas developed after approximately 1. In a small clinical trial, cisplatin treatment for BRCA1-associated breast cancers appears to be promising Byrski et al. Secondary mutations that restore the open reading frame of BRCA2 and its DNA repair function were identified in carboplatin-resistant tumors Edwards et al.
Breast cancer stem cells became enriched on chemotherapy Creighton et al. In several breast cancer cell lines, expansion of CD44hiCD24med cells was associated with herceptin resistance Reim et al. Strategies to target specific pathways required for the maintenance of cancer stem cells are being developed. For example, metformin, a diabetes drug, Hirsch et al.
Understanding the mechanisms underlying such feedback control will provide additional insights into how one might eradicate cancer stem cells. There are several schools of thoughts on the origin of heterogeneity in cancer: In some cases, there may not be a mutation of the tumor suppressor gene, but rather some other mechanism that interferes with its expression or function.
This may include methylation of the gene promoter that suppresses its transcription, an increased rate of proteasomal degradation, or abnormalities in other proteins that interact with the gene product. Tumor suppressor genes have not been extremely useful in diagnostic applications, with the exception of inherited susceptibility genes. Likewise, therapeutic approaches that would entail replacing the function of the lost gene have been stymied by the technical hurdles of efficient gene delivery.
Li-Fraumeni syndrome, a rare familial predisposition to a variety of malignancies including breast cancer, sarcomas, leukemia, and brain tumors as early as the second and third decades of life, has been shown to result from germline alterations of p53, and multiple mutation sites have been reported.
The p53 gene is located on chromosome 17p; it codes a kDa protein that has multiple functions that are regulated via phosphorylation at different sites.
Oncogenes and Tumor Suppressor Genes
Downregulation of the protein is largely through the mouse double minute 2 MDM2 ligase, which usually exists in a complex with p Under normal conditions, p53 acts as a regulating mechanism for cell division. Insults to DNA, such as chemotherapy or gamma irradiation, are associated with rapid increases in cellular content of the protein [ 65 ]. Since most p53 mutations result in increased protein stability, overexpression of p53 has been used as a surrogate of p53 dysfunction.
However, some mutations result in the absence of the protein and may be missed by IHC assays. Abnormalities of p53 expression have been associated with worse prognoses in cases of breast cancer [ 70 ]. Overexpression has been linked to ER negativity, a strong predictor of outcome [ 71 ].
There are conflicting data regarding p53 as a predictor of response to therapy. Although less commonly analyzed, gene mutation analysis of p53 may be more informative than IHC assays of protein levels for this purpose, since p53 is a multifunctional protein and mutations in different domains may have specific consequences. The gene has been ranked as a category II prognostic marker in breast carcinoma [ 72 ].6. Tumour Suppressor Genes (Retinoblastoma and the two hit hypothesis, p53)
It has been demonstrated that p27 has separate binding sites for cyclin and CDK2 and that binding to this complex results in conformational changes of the catalytic cleft of CDK2 [ 73 ]. Many roles of p27 have been proposed, including functions in modulation of drug resistance, cell differentiation, and protection from inflammation [ 74 — 76 ].
Supporting the role of p27 as a tumor suppressor, decreased expression has been documented in a wide range of human cancer cell lines. In breast cancer, diminished expression of p27 is associated with shorter overall survival and shorter time to progression, and this seems to be a stronger independent predictor of outcome than either p53 alterations or tumor grade [ 8081 ].
Stepwise loss of p27 expression may be an event that parallels the transition of a cell from the normal to premalignant to malignant phenotypes [ 82 ]. Some degree of the poor prognosis conferred by loss of p27 expression may be related in part to a role in modulating cell-cell adhesion, and thus, tendency for metastatic spread.
In one series, analyzing tumors smaller than 1 cm in diameter, p27 underexpression was found to be a strong predictor of lymphatic spread [ 83 ]. Affording further support for the importance of p27 in tumor behavior is the finding that antiestrogen compounds result in increased inhibition of CDK activity [ 84 ]. The S-phase kinase-associated protein Skp2 is required for the ubiquitin-mediated degradation of p27 and has been shown to experimentally increase oncogenicity and resistance to antiestrogens in vitro [ 85 ].
BRCA-1 Based upon linkage analysis of families with multiple breast cancers, the locus of an associated gene at 17q21 was reported inand the gene that came to be known as BRCA-1 was subsequently identified in [ 8687 ]. Is has been estimated that approximately 0. Colorectal and prostate cancer incidences may also be increased, but BRCA-1 alterations are not associated with an increased risk of male breast cancer.
BRCA-1 codes a protein of 1, amino acids with several structural domains that hint at its function [ 87 ]. A RING finger domain encodes a protein-binding domain at the amino terminus [ 93 ]. Two repeats in the carboxy terminus are similar to those seen in many DNA repair enzymes including Rad9.
- Oncogenes and tumor suppressor genes: comparative genomics and network perspectives
- Oncogenes and tumor suppressor genes
- There was a problem providing the content you requested
Over individual BRCA-1 mutations have been described, including deletions, substitutions, and insertions. They are found throughout the length of the gene, although some areas do appear to be hot spots for mutation.
It has been suggested that the severity of disease can be linked to the location of the mutation, with mutations involving the amino or carboxy terminus of the gene associated with tumors that display higher proliferation rates [ 96 ].
Whether there is an impact on risk of distant recurrence related to BRCA-1 compared with sporadic cases remains unclear. On average, tumors due to BRCA-1 are higher grade, but there is also an increased incidence of medullary histology, which carries a more favorable prognosis [ 97 ]. Although it is one of the most frequently identified causes for familial breast cancer, BRCA-1 is rarely found to be mutated in sporadic cases.
However, methylation of the gene has been found in sporadic cases and in familial cases with a normal BRCA-1 sequence [ ]. The gene was cloned the following year by the same group [ ]. BRCA-2 protein binds Rad51 and its paralogues needed for the high-fidelity phase of DNA repair, which requires sister chromatid template proofreading. Both genes confer a greater risk for female breast and ovarian cancers when mutated. The Icelandic population carries a separate mutation, del5, at a rate of 0.
BRCA-2 mutation has not been as strongly associated with higher tumor grade as has BRCA-1, but the malignant cells do show less tubule formation. Unlike BRCArelated tumors, no lymphocytic infiltrate is typically seen [ 97 ]. Mutation of BRCA-2 also confers an increased risk for a number of other cancers, including melanoma, prostate cancer, gastric cancer, and cancer of the biliary tree [ 97 ].
Genetic assays to test patients for specific mutations are commercially available, but their use remains somewhat controversial and they should not be applied to the population at large [ ].
Testing should involve genetic counseling and must reflect individual patient preferences and risk trade-offs, since there are no data to suggest that genetically screening patients impacts mortality, even though occurrence is lowered. These malfunctioning genes can be broadly classified into three groups. The first group, called proto-oncogenesproduces protein products that normally enhance cell division or inhibit normal cell death.
The mutated forms of these genes are called oncogenes. The second group, called tumor suppressorsmakes proteins that normally prevent cell division or cause cell death. The third group contains DNA repair genes, which help prevent mutations that lead to cancer. Proto-oncogenes and tumor suppressor genes work much like the accelerator and brakes of a car, respectively.
The normal speed of a car can be maintained by controlled use of both the accelerator and the brake. Similarly, controlled cell growth is maintained by regulation of proto-oncogenes, which accelerate growth, and tumor suppressor genes, which slow cell growth.
Mutations that produce oncogenes accelerate growth while those that affect tumor suppressors prevent the normal inhibition of growth. In either case, uncontrolled cell growth occurs. Oncogenes and Signal Transduction In normal cells, proto-oncogenes code for the proteins that send a signal to the nucleus to stimulate cell division.
These signaling proteins act in a series of steps called signal transduction cascade or pathway Fig.
Oncogenes and tumor suppressor genes | American Cancer Society
Signal transduction pathway See the Genetics and Development unit. This cascade includes a membrane receptor for the signal molecule, intermediary proteins that carry the signal through the cytoplasm, and transcription factors in the nucleus that activate the genes for cell division. In each step of the pathway, one factor or protein activates the next; however, some factors can activate more than one protein in the cell. Oncogenes are altered versions of the proto-oncogenes that code for these signaling molecules.
The oncogenes activate the signaling cascade continuously, resulting in an increased production of factors that stimulate growth. For instance, MYC is a proto-oncogene that codes for a transcription factor. Mutations in MYC convert it into an oncogene associated with seventy percent of cancers. RAS is another oncogene that normally functions as an "on-off" switch in the signal cascade. Mutations in RAS cause the signaling pathway to remain "on," leading to uncontrolled cell growth.
About thirty percent of tumors - including lung, colon, thyroid, and pancreatic carcinomas - have a mutation in RAS.