Breast cancer occurs when cells proliferate uncontrollably in breast tissue Breast cancer is the most common cancer among women. Breast cancer occurs when cells proliferate uncontrollably in breast tissue. This is due to two genes and their protein products expressed specifically in breast tissue: BRCA1 and BRCA2. BRCA2 mutations not only increase a woman’s risk for breast cancer, but also their risk for ovarian cancer with age. An exponential growth occurs with age where the older you get, the much more you are at risk of getting breast cancer. Men are also at risk of getting breast cancer but it is significantly less common in men than in women. Most breast cancers begin in the ducts that carry milk to the nipple. Some start in the glands that make breast milk. There are also other types of breast cancer that are less common. Breast cancer spreads once the cells get into the blood or lymph system. Many cases of breast cancer extend into the shouder and arm pit where the axillary lymph nodes extend from the breast.

BRCA2 is a tumor suppressor gene responsible for DNA repair BRCA2 is a human tumor suppressor gene found in all humans. BRCA2 is in all cells but is expressed in human breast tissue. The BRCA2 protein is responsible for DNA repair. Specifically, the BRCA2 protein is responsible for double stranded DNA repair. If the DNA cannot be repaired, the BRCA2 protein is responsible for destroying the cell in order to prevent proliferation and cancer. A notable difference between the BRCA1 and BRCA2 genes is the BRCA2 is on Chromosome 13 while BRCA1 is located on chromosome 17. Specifically, the BRCA2 is known as a caretaker gene. Caretaker genes encode products that stabilize the genome. Mutations in caretaker genes lead to genomic instability, such as changes in nucleic acid sequences, chromosomal rearrangements, or aneuploidy. This is different from a gatekeeper gene, which encodes products that prevent growth of potential cancer cells and prevent accumulation of mutations that directly lead to increased cellular proliferation.

BRCA2 was discovered in breast cancer tumors of patients without BRCA1 mutations BRCA1 was discovered in 1990, but there were still families that were affected by breast cancer that was not attributed to a BRCA1 mutation. Table 1 is a list of the families used in the study with female breast cancer, male breast cancer, and ovarian cancer. The Lod score is a statistical estimate of whether two loci are likely to lie near each other on a chromosome and are, therefore, likely to be inherited as a package. A Lod score of 3 or lower is good, negative lod scores mean the linkage is less likely. Since each of these have a negative lod score to different degrees, they are still less likely to be linked to BRCA1. There are also sporadic cases. Families were then genotyped with polymorphic microsatellite repeat markers. These markers found significance at D13S263 and D13S260 to provide evidence that there was a susceptibility gene on chromosome 13. Table 2 shows lod scores for positions on chromosome 13 with D13S260 being the most likely position of a susceptibility gene on chromosome 13. Table 3 shows haplotypes of each individual in a certain family in the study. For each family, there was a haplotype shared by all affected individuals on chromosome 13, proving the location of the new susceptibility gene BRCA2.

Mice knockouts discovered that BRCA2 is directly involved in double strand break repair BRCA-deficiency results in chromosomal instability and increased sensitivity to DNA-damaging agents in cultured mouse cells. BRCA1 appears to be more of a signal integrator, linking together sensors and response mechanisms of several types of DNA damage. In contrast, BRCA2 is though to be more directly involved in homology-directed double strand break repair, as it mediates the formation of a RAD51-DNA nucleoprotein filament that catalyzes strand invasion during homologous repair. The BRCA2 gene is different from mice and humans but each still has the RAD51 gene. Many knockout and mutations have been created to see the results of the knockout.

BRCA2 combines with BRCA1 and RAD51 in response to DNA double strand breaks A double strand break in DNA signals ATM and the Fanconi Anemia complex. ATM is a protein kinase activated by double strand breaks. The Fanconi anemia complex monoubiquitinates its downstream targets: FANCD2 and FANCI. ATM activates CHEK2 and FANCD2 via phosphorylation and CHEK2 phosphorylates BRCA1. Ubiquinated FANCD2 complexes with BRCA1 and RAD51. Along with the different locations of the BRCA1 and BRCA2 genes, they also serve different functions in the pathway. PALB2 brings together BRCA1, BRCA2, and RAD51 at the site of the double strand break. PALB2 means partner and localizer of BRCA2 and is responsible for the connection of BRCA2 with the DNA repairation complex. RAD51 plays a major role in recombinational repair of DNA during double strand break repair. BRCA2 binds the single strand DNA and directly interacts with the recombinase RAD51 to stimulate strand invasion.

BRC repeats of BRCA2 attach to Rad51 monomers to connect it to DNA RAD51 interacts with the BRC repeat region of BRCA2 which matches with the RAD51 monomers. The proposed model is that the BRC repeat provides an assembly line of RAD51 monomers, and that the C-terminus of BRCA2 binds ssDNA, providing a means to displace RPA and allow the orderly assembly of the RAD51 filament. In the absence of BRCA2, critical events in the initiation of homologous recombination are impaired, and repair errors accrue rapidly with each cell cycle.

All germ line BRCA2 mutations identified to date have been inherited, suggesting the possibility of a large “founder” effect Population or subgroup BRCA2 mutation(s) Ashkenazi Jewish 6174delT Dutch 5579insA Finns 8555T>G, 999del5, IVS23-2A>G French Canadians 8765delAG, 3398delAAAAG Hungarians 9326insA Icelandics 999del5 Italians 8765delAG Northern Irish 6503delTT Pakistanis 3337C>T Scottish Slovenians IVS16-2A>G Spanish 3034delAAAC(codon936), 9254del5 Swedish 4486delG All germ line BRCA2 mutations identified to date have been inherited, suggesting the possibility of a large “founder” effect in which a certain mutation is common to a well-defined population group and can theoretically be traced back to a common ancestor. Given the complexity of mutation screening for BRCA2, these common mutations may simplify the methods required for mutation screening in certain populations. Analysis of mutations that occur with high frequency also permits the study of their clinical expression. A striking example of a founder mutation is found in Iceland, where a single BRCA2 mutation accounts for virtually all breast/ovarian cancer families. This frame-shift mutation leads to a highly truncated protein product. In a large study examining hundreds of cancer and control individuals, this 999del5 mutation was found in 0.6% of the general population. Of note, while 72% of patients who were found to be carriers had a moderate or strong family history of breast cancer, 28% had little or no family history of the disease. This strongly suggests the presence of modifying genes that affect the phenotypic expression of this mutation, or possibly the interaction of the BRCA2 mutation with environmental factors. Additional examples of founder mutations in BRCA2 are given in the table.

Olaparib combats the BRCA2 mutations by helping cause cell death There is almost always a loss of heterozygosity in BRCA1 and BRCA2 carrier cancers, characteristic of a tumor suppressor gene. It is difficult to restore inhibition with a molecular target in tumor suppressor genes. Synthetic lethality experiments have been run in regards to inducing apoptosis and preventing proliferation in cells with a BRCA1 or BRCA2 mutation. Synthetic lethality is when a mutation or inhibition of two pathways leads to cell death when either alone would not. The poly(ADP-ribose) polymerase (PARP) family of proteins also has important roles in DNA repair. PARP-1 is involved in the repair of single-stranded DNA breaks. PARP inhibition and BRCA deficiency result in defects in more than 1 DNA repair pathway which leads to cell death. Oral PARP inhibitor olaparib had low toxicity and demonstrated activity in BRCA1 and BRCA2 mutation carriers. BRCA1 and 2 carriers seem to have differential sensitivity to some chemotherapeutics, including some platinum agents. Somatic mutations in BRCA1 or 2 frequently occur in sporadic ovarian cancer as do other molecular changes that may impair homologous repair. Deficiencies in BRCA1 or BRCA2 may be associated with an improvement in progression-free survival. Olaparib prolongs progression-free survival by 4 months. PARPs help in sporadic ovarian and breast cancers if they are BRCA-like (negative expression of oestrogen receptor, progesterone receptor, and HER2)

Sources https://www.cancer.org/cancer/breast-cancer/about/what-is-breast- cancer/_jcr_content/par/image.img.gif/1482250472378.gif http://www.publichealth.org/wp-content/uploads/2014/12/Cancer-Image-I.-Leading-Cancers.png http://www.nature.com/onc/journal/v22/n37/images/1206678f3.jpg https://image.slidesharecdn.com/basicintroductiontotheroleofgeneticsinbreastcancerdevelopmentandtreatme nt-13045837154577-phpapp02/95/basic-introduction-to-the-role-of-genetics-in-breast-cancer-development- and-treatment-15-728.jpg?cb=1304565800 https://upload.wikimedia.org/wikipedia/commons/2/2e/BRCA_Genes.svg https://upload.wikimedia.org/wikipedia/commons/c/c2/PBB_Protein_BRCA2_image.jpg https://upload.wikimedia.org/wikipedia/commons/d/dc/Homologous_recombinational_repair_of_DNA_doubl e-strand_damage.jpg Br J Clin Pharmacol. 2016 Jan; 81(1): 171–173. Published online 2015 Oct 24. doi: 10.1111/bcp.12761