The functional role of TP53 gene in development of breast cancer

Abstract

The incidence of breast cancer has risen steadily over the last half a century, partially due to earlier detection. Nevertheless, the mortality rate has remained relatively constant (27 per l00.000 women). Although we are beginning to understand the risk factors for breast cancer, including environmental sources (e.g. mutagen exposure) and personal choices (e.g. late first childbirth age and high dietary fat intake), the further identification of mechanisms underlying the development and progression of breast cancer is of major public health importance.

The activation of oncogenes has been well described as one possible mechanism to transform normal cells, including breast. Now it has become clear that the inactivation of various tumor suppressor genes, which can be thought of as “brakes” of cell growth, is at least as important in the development and progression of breast cancer. Tumor suppressor genes are considered to act mostly in a recessive fashion, i.e. some abnormality must affect both gene alleles. The classical inactivation of tumor suppressor genes, i.e. the Knudson “Two-Hit” hypothesis (Knudson, 1971), is caused by tumor suppressor gene loss due to chromosomal loss of one allele, and mutation of the other remaining allele. Chromosomal loss is mostly analyzed by karyotypic studies or loss of heterozygosity (LOH) studies, and mutations are most frequently studied by sequencing of the gene of interest or by single strand chain poly-morphism analysis (SSCP). In many cases, mutations can result in truncated protein products which are easy to detect. However, recently it has been shown that functional inactivation of tumor suppressor genes can be caused by many other epigenetic mechanisms besides mutation, including hypermethylation (Baylin et al. 1998, Foster et al. 1998), increased degradation (Storey et al. 1998), or mislocalization (Chen et al. 1995, Moll et al. 1992, Takahashi and Suzuki 1994 ).

The function and role of tumor suppressor genes have been elucidated by many investigators through a combination of a number of cell biological as well as biochemical methods. Kinzler and Vogelstein (1997) have recently proposed a new system to categorize tumor suppressor genes as “gatekeepers” and “caretakers”. Gatekeepers are tumor suppressor genes which are directly involved in controlling proliferation by regulating cell cycle checkpoints (e.g. Rb and the INK family of cdk inhibitors). Mutations of these genes usually result in high penetrance. In contrast, caretakers are of rather low penetrance, and have an indirect effect on growth. They are responsible for genome integrity, and changes in such genes lead to genome instability.

In the past several years we have seen an explosion of information in the field of breast cancer genetics, with regard to the identity of tumor suppressor genes that are mutated in sporadic breast cancer as well as those that are inherited in mutant forms, giving rise to a familial predisposition to cancer. In this research we will summarize informations and concentrate on tumor suppressor gene which has been proven to play a role in breast cancer in vivo.

Among gatekeepers genes, P53 gene is the most well known, located on chromosome band 17p13, p53 encodes a 53-Kd multifunctional transcription factor that regulates the expression of genes involved in cell cycle control, apoptosis, DNA repair and angiogenesis. In breast cancer, most studies have shown that P53 mutation or down-regulation is associated with adverse prognosis. Also P53 wild-type protein plays an important role in cells as is shown by its fine regulation at different levels P53 is mutated in almost 30% of cases, with a higher frequency in some tumor subtypes. TP53 mutation is reported to be a factor for good prognosis in some studies, while in others it is a factor for poor prognosis. These different results can be explained based on studies in different tumor types with different therapy regimens. P53 plays a key role in integrating cellular response to damaging agents.

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The functional role of TP53 gene in development of breast cancer