Breast And Ovarian Cancer Biology Essay


Genomic is the study of genome of organisms, the set of inherited material found in every cell of the body while proteomic is the study of protein and the proteome, the collection of individual proteins in given cells, as well as the entire body. Both are closely related to each other in scientific fields but are still 2 different fields of study.

In order to differentiate genomics from proteomics, a metaphor of library will be use. The genome in this case will be the card catalogue, which list out everything that should be in the library. Follow by proteome which will be the actual contents of the library. Genome researchers are interested in seeing the traits the genome codes for, understanding the role of DNA that doesn't appear to code for anything, which is something like cards referencing long-lost books and books that have been checked out, and in looking at how traits are inherited.

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Proteomics researchers will be interested in how the genome actually expresses in the body. The process of protein formation, protein production interferers and interrupters, source of protein variants, and related matters. Genomics and proteomics are certainly linked, as the genome provides the blueprints for the proteome. Through mapping and researching proteins, researchers are provided with information on how the same gene can express differently in different individuals, and also adds insight and understanding for researchers interested in learning how proteins behave in the body.

These work can also be applied to fields like pharmacology and medicine, where people put the information they are collecting in the lab into real world use in the field.

Hii Khang Jiet PC080725452 12th October 2010

In such condition, we'll be using breast and ovarian cancer as a sample. There are 2 major genes which associated with susceptibility to breast and ovarian cancer - breast cancer susceptibility gene 1 (BRCA1) and breast cancer susceptibility gene 2 (BRCA2) - have been identified to date. Mutations in either one of these genes contributes to a lifetime risk of breast cancer of between 60-85% and a lifetime risk of ovarian cancer of between 15%-40%. However, mutations in these genes account for only 2-3% percent of all breast cancers, and susceptibility alleles in other genes, such as TP53, PTEN, and STK11/LKB1, are even less common causes of breast and ovarian cancer.

General information about cancer is that it is a class of disease which a cell, or a group of cells display uncontrolled growth, invasive properties, and sometimes metastasis. Cancer will affect two general classes of genes, the cancer promoting oncogenes and the tumour suppresser genes. The cancer-promoting oncogenes, a type of cell upon mutated or expressed at high levels, involving in turning a normal cell into a tumour cell bypassing the apoptosis, are typically activated in cancer cells, giving those cells new properties, such as hyperactive growth and division, protection against programmed cell death, loss of respect for normal tissue boundaries, and the ability to become established in diverse tissue environments. Tumour suppressor genes, a cell which are involves in apoptosis, are inactivated in cancer cells, resulting in malfunctioning in those cells, such as accurate DNA replication, control over the cell, orientation and adhesion within tissues, and interaction with protective cells of the immune system.

A brief introduction to is that BRCA1 is a human tumour suppressor gene, which produces a protein, called breast cancer type 1 susceptibility protein which helps in repairing damaged DNA and destroy non-repairable DNA cells. If BRCA1 itself is damaged, damaged DNA will not be repair and thus increases risks for cancers. It is located on the long (q) arm of chromosome 17 at band 21, from base pair 38,429,551 to base pair 38,551,283 (Build GRCh37/hg19).

Hii Khang Jiet PC080725452 12th October 2010

The function of BRCA1 involves repairing damages in double-strand DNA as they continue to break resulting in unwanted damage, which the strands can break alone or together simultaneously. BRCA1 act as part of a protein complex which repairs DNA when both strands are broken. BRCA1 participates in double strand repairing which is a homologous recombination, a type of repairing process that the proteins utilize homologous intact sequence from a sister chromatic or from the same chromosome, which varies upon cell cycle as a template. The DNA repair takes place along the DNA in the cell nucleus, wrapped around the histone. Apart from BRCA1, some other proteins will also join in such repairing action at the complex side.

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The BRCA1 protein will interact with another protein call RAD51, a type of 339-amino acid protein that plays a major role in homologous recombination of DNA, during repair of DNA double-strand breaks. These damages can be due to natural radiation or other exposures, as well as when chromosomes exchange genetic material.

BRCA1 will directly bind to DNA, as it has higher affinity for branched DNA structures which will inhibit the nuclease activity of the MRN complex as well as the nuclease activity of Mre11 alone. Such action explains the role of BRCA1 to promote higher fidelity DNA repair by non-homologous end joining (NHEJ). BRCA1 also co-localizes with γ-H2AX (histone H2AX phosphorylated on serine-139) in DNA double-strand break repair foci, indicating it may play a role in recruiting repair factors

As for BRCA2, Breast Cancer Type 2 susceptibility protein, it has more or less the same function as BRCA1, for which proteins encoded by this gene are involved in the repair of chromosomal damage with an important role in the error-free repair of DNA double strand breaks. It is located on the long (q) arm of chromosome 13 at position 12.3 (13q12.3), from base pair 31,787,616 to base pair 31,871,804.

Hii Khang Jiet PC080725452 12th October 2010

The different structures of the BRCA1 and BRCA2 genes but interrelated functions are what amazed researchers till today. The proteins evolved from both genes are essential for repairing damaged DNA. The BRCA2 protein binds and regulates the protein produced by the RAD51 gene to fix breaks in DNA caused by natural and medical radiation or other environmental exposures. It might also happen when chromosomes exchange genetic material during a special type of cell division that creates sperm and eggs (meiosis).

These three proteins, BRCA1, BRCA2 and RAD51, play a vital role in repairing DNA, maintaining the stability of the human genome and prevent dangerous gene rearrangements that can lead to hematologic cancers.

Postulates about DNA-sequence variants that confer a small but appreciable enhanced risk of cancer have been validated with the recent discovery of the 1100delC mutation in the cell-cycle-checkpoint kinase gene (CHEK2). This mutation was found in 1.1% of women without breast cancer, 1.4% of women with a personal but no family history of breast cancer, and 4.2% of index patients from 718 families in which two or more members had been given a diagnosis of breast cancer before the age of 60 years but in which there was low or no detectable BRCA1 or BRCA2 mutation. This mutation increases the risk of breast cancer among women which at worst doubles it and increases the risk among men by a factor of 10. CHEK2, a vital component of the cellular machinery which recognizes and repairs damaged DNA, is activated through phosphorylation by the checkpoint gene ATM, Ataxia telangiectasia mutated - a serine/ threonine protein kinase (EC which is recruited and activated by DNA double-strand breaks, and in turn activates BRCA1. The postulates of mutation of ATM in the predisposition to the early onset of breast cancer remains controversial, but apparently some mis-sense mutations do increase susceptibility to breast cancer in humans.

Hii Khang Jiet PC080725452 12th October 2010

There are convincing evidences that additional high-penetration genes that increase susceptibility to breast cancer exist. In return, it has been suggested that apart from BRCA1 and BRCA2, high-penetration genes that confer susceptibility to ovarian cancer do not exist. An ovarian-cancer-susceptibility locus on chromosome 3p22-25 has putatively been identified, but this finding has yet to be confirmed.

Many additional genetic variants in low-penetration susceptibility alleles may moderately increase the risk of breast cancer, ovarian cancer, or both. Such genetic variants are quite common in the population than are high-penetration gene mutations and, thus, in aggregate may make a substantially greater contribution to breast and ovarian cancer in the population than mutations in high-risk genes. However, genetic heterogeneity and the rarity of high-penetration genes make both high-penetration and low-penetration genes difficult to identify.

Since a few years ago, researchers have extended their study to more patients and report improved sensitivity and specificity of the diagnostic test. They have also used the technique to examine breast and cancer. Within less than two years after scientists reported a simple blood test that successfully detects ovarian cancer even in its early stages, clinical laboratories are gearing up to make the test available which is possible to detect an breast and ovarian tumour while it is still small and potentially curable. Patients with breast and ovarian cancer show very few symptoms in the early stages of tumour growth, and by the time symptoms appear the disease has often progressed so far that high chances they are in the final stage and the patient's survival chances are poor. More than 80% of breast and ovarian cancer patients are diagnosed with late stage disease and only 35% of these patients survive for five years. In contrast, 95% of women survive if they are lucky enough to be diagnosed in the early stages.

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Hii Khang Jiet PC080725452 12th October 2010

FDA (Food and Drug administration) and NCI (National Cancer Institute) in cooperation with Correlogic (a research cooperation) planned a series of clinical trials to assess how well the test performs in diagnosing and staging breast and ovarian cancer and to seek FDA approval for the widespread use of the technology. It was a breakthrough in cancer diagnostics. The researchers reported in Lancet that a simple blood test correctly diagnosed ovarian cancer in a study of 116 women.

An initial trial was conducted on 1500 women with a history of breast and ovarian cancer to see whether the test can detect cancer recurrence. One of the tests for assessing breast and ovarian cancer recurrence is the CA-125 test, which measures the levels of a biomarker, a protein called CA-125, in patients who have survived breast and ovarian cancer. The CA-125 test is relatively insensitive in detecting breast and ovarian cancer in early stages. However the test result in failure to detect early stage, and showing only at late stage which is fatal. The observations involves value of pattern recognition in diagnosis, Haptoglobin α-subunit complementary to CA125 in the diagnosis, value of the other biomarkers such as CA19.9, CA15.3, and TAG72 in the diagnosis of the cancer, development of a multivariate model with 3 additional biomarkers - a polipoprotein A1; a truncated form of transyretin; and inter-α-trypsin inhibitor heavy chain H4, and combination of soluble mesothelial related marker with biomarker for diagnosis cancer. As a result, it shown that CA19.9 has a high sensitivity for the mucinous histotype, where as CA125 is useful in terms of monitoring therapy aside from involving in ovarian, breast and cervical cancer. As for the 3 additional biomarkers, only inter-α-trypsin inhibitory chain H4 show up regulated result as the other show down regulated result.

Hii Khang Jiet PC080725452 12th October 2010

This promising prospect for the detection of cancer in early stages comes from the emerging field of clinical proteomics which is the study of patterns of proteins in human blood or other tissues. The proteomic test were then use to test if it can do as well as CA125 in predicting the cancer recurrence and if the test can accurately discern between breast and ovarian cancer and women who present with a benign pelvic mass. The tests involved include certain test for lung cancer as control and observe material were biomarkers identification for use in environmental health, comparison of protein profiles for invasive versus low malignancy potential breast and ovarian cancer using laser capture micro-dissection, biomarkers in cancer screening/ detection, protein profiling with surface enhanced laser de-sorption/ ionization (SELDI) in breast cancer, tumour cells and tumour biomarkers in small cell lung cancer - multiple biomarkers including circulating tumour cells, biomarkers selection and validation - clinical endpoint evaluation and application, relation of haptoglobin α-subunit and breast and ovarian cancer, colorectal cancer, drug development and toxicology, identification and validation of biomarkers for lung cancer, protein profiling in intra-amniotic infection, and up/ down regulation of biomarkers in ovarian and breast cancer - development and validation of multi-variate model.

A significant hope for new diagnostic tests had been offered by proteomics as it can be used to detect a pattern of proteins that are being produced by cancer cells anywhere in the body. Such proteins are shed into the bloodstream and easily picked up by the blood test. Thus resulting in cancer can be detected without having to biopsy individual tissue samples, which is a major advantages and progress. Along with gene test, it offers a long-term forecast of disease risk, the identification of breast and cancer patient at early stage is easier and faster compare to before.

Hii Khang Jiet PC080725452 12th October 2010

Based on the research, the researchers first developed a characteristic cancer profile by comparing patterns of proteins in the blood of healthy individuals to those of patients known to have ovarian cancer in the primary and original study. This information is then used to identify which patients had ovarian cancer and which did not.

The proteomic test carries on as it was a success. The tests which were carried on later involve serum proteomics analysis (SELDI), 2-dimensional gel electrophoresis, serum protein analysis and immuno-histocytochemistry review. As a result, a list of more effective biomarkers are found: CA125 + apolipoprotein A1, truncated transthyretin, inter-α-trypsin inhibitory heavy chain H4, CA125 + haoptoglobin α-subunit, CA125 + 4 other biomarkers, 52 kDa FK506 binding protein, Rho G-protein dissociation inhibitory (RhoGD1), glyoxalase 1, CA125 + soluble mesothelin-related marker, haemoglobin, type IV collagen, CD44v6, P53, Ki-67, tumour-associated trypsin inhibitor, OP-18, PCNA, triosephosphate isomerase, elongation factor-2, GST all up regulated, TM2 and laminin c down regulated. During a research, researchers analyzed the proteins in blood from 50 women with ovarian cancer and 66 healthy women, the test correctly identified all of the cases of ovarian cancer, including 18 patients with very early disease. The test correctly identified among 66 people, 63 individuals with no disease and incorrectly indicated that three had cancer.

Hii Khang Jiet PC080725452 12th October 2010

As mentioned before, DNA is unstable, and alterations occur from time to time through three major causes: through exposure to environmental agents; effect of by-products of normal cellular metabolism; and through continuous and spontaneous disruption of chemical bonds in DNA. This causes a variety of lesions including base modifications, single strand breaks, double strand breaks, and intra-strand or inter-strand cross-links. 4 principals and partially overlapping DNA repair mechanisms are involved in these lesions repair mechanism and maintaining genomic integrity in mammals. These are base-excision repair (BER), nucleotide-excision repair (NER), mismatch repair (MMR), and re-combinational repair with homologous recombination (HR) and non-homologous end-joining (NHEJ). Repair of single strand breaks involves BER, NER, and MMR while repair of double strand breaks involves HR and NHEJ. Furthermore, some damage to DNA can be repaired directly, which for instance, methylation of guanine bases is directly reversed by the protein O6-methylguanine-DNA methyltransferase (MGMT).

Alterations of a single DNA strand, including single strand breaks, are mainly endogenous and are the most common DNA aberration. They are repaired through intact complementary strand as a template by BER, NER, and MMR. About 10 thousands spontaneous single strand breaks occur in each cell every day. The BER pathway is a vital repair mechanism of these lesions and involves a family of enzymes called PARP. PARP was first described in 1963. There are 17 members of the PARP superfamily described. PARP1, which is a vital member of this family, which its primary function is to bind to single strand breaks as a component of the BER pathway. PARP1 which catalyses the formation of large branched chains of poly-(ADP)-ribose from its substrate nicotinamide adenine dinucleotide (NAD+). These chains recruit other DNA repair proteins. In addition to BER, PARP1 might also be involved in NER. Thus, it shows that PARP1 play a pivotal role in repair of damaged DNA and in stabilisation of the genome.

Hii Khang Jiet PC080725452 12th October 2010

Double strand breaks can be due to X-rays or chemicals during repair of inter-strand cross-link and during replication of single strand breaks converted into double strand breaks at replication forks and repaired by HR as mentioned as above. Double strand breaks are potentially more of a problem to a mammalian cell than single strand breaks because both strands are affected and the complementary DNA strand is not available as a template. Double strand breaks are primarily repaired by HR, which tends to be error-free, and NHEJ, which is more prone to error and can lead to changes in the DNA sequence at the break site

Poly-(ADP-ribose)-polymerase (PARP), a type of protein involved certain cellular processes involving DNA repair and apoptosis, programmed cell death. 2 types of nuclear PARP can be activated by DNA damage: PARP1 and PARP2. The vital role of PARP1 enzyme in single strand breaks repair described in 'Single DNA strand repair including single strand breaks and role of PARP' section, which deficiency does not seem to be such a problem for non-malignant cells. Certain organisms engineered to be lack of PARP1 enzyme (PARP1−/−) are both viable and fertile, but do not seem to develop early-onset tumours. Even so, conflicting results reported in alternative research paper suggesting that PARP genetic ablation may predispose to mammary cancer. Such 'severe consequences' incident as a result of PARP deficiency can be explained by an understanding of DNA repair mechanisms. The loss of PARP1 activity affects repair of single strand breaks via BER, causing cells using alternative DNA repair pathways. When DNA replication occur, un-repaired single strand breaks are converted into double strand breaks at replication forks and repaired by HR. PARP1 inhibition blocks repair of single strand breaks but repair of double strand breaks is able to proceed, which result in an increase of HR and acts as a very efficient error-free rescue mechanism.

Hii Khang Jiet PC080725452 12th October 2010

PARP2 plays a vital role in almost the same mechanism as PARP1. In a simulation cell line model, it shows that the clonogenic survival of normal human cells is decreased by 20% when both PARP1 and PARP2 proteins are co-depleted with short interfering RNA. The consistent results through the observation of an embryonic lethal phenotype in double PARP1 and PARP2 knockout mice. However, when either one of the BRCA protein is also depleted in this model, the clonogenic survival is decreased by doubly, which is 40%; either one or both when co-depleted will result the same. Greater selectivity can be shown through these results and suggest that specific PARP1 inhibitor could cause less toxicity to normal cells which is vital as since all the current PARP inhibitors are both PARP1 and PARP2 inhibitors.

PARP inhibitor act as a drug that blocks PARP proteins from performing their roles in repairing damaged cancer cells. Recently, Olaparib, a new type of experimental drug which is a PARP inhibitor, has shown promising results against inherited forms of breast and ovarian cancer in two small clinical trials led by scientists at the Breakthrough Breast Cancer Research Unit at King's College London.

Olaparib acts as an inhibitor for PARP enzyme and is one of the first PARP inhibitors. Patients with BRCA1 or BRCA2 mutations may be genetically predisposed to develop certain forms of cancer, and are often resistant to other forms of cancer treatment, such as Chemotherapy and radiation that works by breaking the DNA of cells so that they may not regenerate nor reproduce, but this might lead cancers a unique vulnerability, as the cancer cells have increased reliance on PARP to repair their DNA and enable them to continue divide even after recover from the assault of cancer treatments. This suggests that drugs which are selectively PARP inhibitors may be of significant benefiting those patients whose cancers are susceptible to such treatment. Clinical trials are currently being done to see if merging PARP inhibitors with other treatments , can block PARP protein from damaged cancer cells.