The Evolution, Functions and Applications of the Breast Cancer Genes BRCA1 and BRCA2

Abstract

Abstract. BRCA1 and BRCA2 are Breast cancer susceptibility genes 1 and 2 (BRCA1 and BRCA2) are found in a wide variety of organisms and help stabilize the genome. BRCA2 homologs and orthologs are found in organisms across three kingdoms: animal, plant, and fungi whereas BRCA1 homologs and orthologs are only found in animal and plant kingdoms. While not every organism possesses either or both of the genes, a vast majority do, indicating that the presence of BRCA1/2 genes dates back to 1.6 billion years ago when the three kingdoms were first diverging.Both genes are tumor suppressors and are highly involved in ensuring genome stability. BRCA1 is involved in both the checkpoint activation and in DNA repair, while BRCA2 regulates homologous recombination. BRCA1 and BRCA2 mutations are the cause of most hereditary breast cancer, and are responsible for up to 10% of all breast cancer. The risk for developing breast cancer is 80% with BRCA1 mutations and 60% with BRCA2 (1). While BRCA1 and BRCA2 are notoriously linked to an elevated risk of breast cancer, it has been found that they are also associated with an elevated risk for ovarian, pancreatic, endometrial, prostate, stomach, laryngeal, and fallopian tube cancers (2, 3). Breast cancer has been reported in other mammals including rodents, carnivores, and primates (4). This would suggest that BRCA1/2 mutations would affect functions that are unique to mammary tissue and mammals in general, however, that is not the case. The function of both of these genes results in genome stability. BRCA1/2 are both required for homologous recombination. BRCA1 is also involved in cell cycle checkpoints.Through examining BRCA1/2 in other organisms, the functional domains can be identified that assist in determining if mutations are cancer-causing. Additionally, this allows us to learn more about the function of these genes and possible cures and treatments. Years of research and investigation of various organisms for BRCA1/2 homologs has contributed to our knowledge of BRCA1/2's role in cancer and the evolution of these genes (Table I). BRCA1 and BRCA2 FunctionThe initial search for a gene responsible for hereditary breast cancer resulted in finding BRCA1 that is responsible for DNA repair and checkpoints in the cell cycle (5). Further inquires into genes susceptible to breast cancer found BRCA2 which has a role in homologous recombination (6). It has been found that homozygous mutations in either of these genes is lethal and development stops embryonically. Both BRCA1 and BRCA2 lead high-fidelity repair through homologous recombination (7). 293

The Role of Circulating Adiponectin and SNP276G>T at ADIPOQ Gene in BRCA-mutant Women

“…Adiponectin exerts several physiological effects involving different cell pathways and producing various biological results such as modulation of inflammatory responses, of lipid and glucose metabolism, function of vascular endothelial cell adhesion molecules, and characteristics of extracellular matrix components, but until now there was little information on adipokines and cellular BRCA-mediated pathways. BRCA proteins are known to play protective roles against the carcinogenic effects of estradiol (35). Therefore, since inflammatory adiponectin influences the sex hormone mechanism of tumorigenesis via stimulation of estrogen production by aromatase, this effect might be important in BRCA-mutant women (36).…”

Identifying a BRCA2 c.5722_5723del mutation in a Han-Chinese family with breast cancer

“…It encodes a protein consisting of 3418 amino acid residues. The exon 11 encodes more than 50% of the entire protein [20]. The BRCA2 protein plays a major role in homologous recombination (HR) that primarily repairs replication-associated DNA double-strand breaks (DSBs) during the S and G2 phases of the cell cycle [21].…”

Hyperlipoproteinemia (a) is associated with breast cancer in a Han Chinese population

“…[ 4 , 5 ] Approximately 5% to 10% of breast cancer have a hereditary cause, and most of these are accounted for by harmful mutations in 2 tumor suppressor genes: BRCA1 and BRCA2. [ 6 , 7 ] In clinical settings, it is well recognized that breast cancer is a heterogeneous disease with different histological presentations and treatment responses. To guide prognostication and treatment regimen, breast cancer is traditionally divided into 5 molecular subtypes: luminal A, luminal B, HER2, triple-negative/basal-like, and normal-like.…”