Tumor suppressor genes in breast cancer.

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 100 000 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 polymorphism 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 & 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 & 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. The best characterized examples are repair genes, such as MSH2 in hereditary non-polyposis colon cancer (HNPCC) (Fishel & Wilson 1997). It is likely that more categories will follow, for instance ‘landscaper’ for genes which are involved in epithelial-stromal and epithelial-epithelial interactions (e.g. E-cadherin and α-catenin) (Bullions et al. 1997). 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 review we will summarize this information, and concentrate on tumor suppressor genes which have been proven to play a role in breast cancer in vivo.