Lab Anim Res.  2010 Dec;26(4):323-330. 10.5625/lar.2010.26.4.323.

Gene Mutations in Animal Models: Do Tumor Suppressor Genes, brca1 and brca2, Play a Role in Ovarian Carcinogenesis?

• Yi BR
• Hwang KA
• Choi KC

• KMID: 2114699
• DOI: http://doi.org/10.5625/lar.2010.26.4.323

Abstract

Ovarian cancer is the most lethal cause of death from gynecological malignancies in the Western world. Over 90% of human ovarian cancers arise in the ovarian surface epithelium (OSE). The OSE surrounding the ovary is simple mesothelium and squamous to flat-cubobidal mesothelial cells. This cell type of ovary has both epithelial and mesenchymal potential. Also OSE cells are regulated by many factors such as cytokines, growth factors, and multiple hormones. Nevertheless OSE function is poorly understood. In particular, ovarian cancers are closely related with hereditary predisposition. Hereditary ovarian tumors are commonly associated with mutations in tumor suppressor genes such as brca1 and brca2 genes. These genes play a role in maintenance of genome integrity, DNA repair, cell cycle control and apoptosis. Mutations in brca1 and/or brca2 may lead to carcinogenesis through distinct molecular pathways like estrogen-mediated proliferation, the presence of a p53 mutation, and the modulation of the activity of NF-kB. Especially the dysfunction of brca1 triggers the inactivation of p53 and a higher proportion of a p53 mutation is commonly linked to brca-linked ovarian tumorigenesis. The dysfunction of brca1 and/or brca2 can arise from multiple mechanisms in the regulation of both JNK and ERK1/2 signaling. For more effective diagnosis and therapy of ovarian cancer, the role of brca1 and/or brca2 in ovarian cancer has to be distinctively elucidated by the animal models in which the gene functions are deleted in mouse OSE cells and by the mechanisms by which these genes affect ovarian carcinogenesis.

Keyword

Ovarian surface epithelium; tumor suppressor gene; brca1/2; animal models

MeSH Terms

Animals
Apoptosis
Cause of Death
Cell Cycle Checkpoints
Cell Transformation, Neoplastic
Cytokines
DNA Repair
Epithelium
Female
Genes, BRCA2
Genes, Tumor Suppressor
Genome
Humans
Intercellular Signaling Peptides and Proteins
Mice
Models, Animal
NF-kappa B
Ovarian Neoplasms
Ovary
Western World
Cytokines
Intercellular Signaling Peptides and Proteins
NF-kappa B

Figure

• 

  Figure 1. Scheme of ovarian cancer development derived from brca1 mutation in OSE cells. The ovary is covered with simple OSE cells. These OSE cells are ruptured by ovulation and destroyed to release eggs. Ruptured OSE cells are recomposed by OSE cell proliferation. At this time, OSE cells can be created in an inclusion cyst. These inclusion cysts can more effectively be contacted with growth factors or stromal hormones by stromal layers. At results, brca1 gene appears to lead to mutation and inhibition of brca1 protein synthesis. When DNAs are damaged, deficient bara1 protein brings about scarcity of DNA repair function. Ultimately, this reason may cause the initiation of various types of ovarian tumors, i.e., serous, endometriod, mucinous, or clear cell ovarian tumors.

Reference

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