Suppressor genes in breast cancer: an overview.

Abstract

It is apparent that multiple genetic events occur in the development and progression of breast cancer. From the limited data available, no consistent temporal pattern of mutational events is required. This conclusion is consistent with data in colorectal carcinoma, where the number of mutational events, and not the order, appears to be relevant. Several authors have questioned whether the multiple mutational events occur independently or whether significant associations were evident. Cropp et al. postulated that two sets of mutational events occurred simultaneously in a higher degree of breast tumors than expected based on chance: Set 1 consisted of deletions on 11p, 17p, 18q, and int-2 and myc amplifications; set 2 consisted of 17q, 1p, and 3p deletions. Sato et al., analyzing another tumor cohort for simultaneous mutations, noted a correlation of 17p and 16q deletions, 13q and 17p deletions, and 17p deletion with erbB-2 amplification. Clearly, concordant data on this issue will require the use of large breast tumor cohorts for a comprehensive set of probes. The reasons why mutations to specific genes on different chromosomes tend to occur coordinately is unknown, but may involve common flanking and/or intron sequences at high risk for certain types of mutational events. Another interesting question is the degree to which alterations, but not homozygous inactivation, of suppressor genes occur and its phenotypic consequences. In this chapter, evidence was presented for the amplification of a DCC allele in breast cancer and for variable RB protein expression in breast tumors as a consequence of allelic deletion. For many of the metastasis suppressor genes, a simple reduction in their expression, or an alteration in their expression over the normal cellular regulatory controls, may be sufficient to fuel the metastatic process. The data suggest a more complex regulation of the cancer phenotype by suppressor genes than by recessive inactivation alone. Why do many sporadic cancers, including breast cancer, appear to require alterations to multiple suppressor genes, as compared to diseases such as retinoblastoma, where a single suppressor gene appears to control the cancer phenotype? The answer to this question is unknown, but most theories are based on the hypothesis that suppressor genes act to control cellular responses to either other cells or signals in the microenvironment. In retinoblastoma all cells can carry a germ-line mutation. Cells carrying the RB mutation can interact with both the embryonic and differentiated microenvironments; the specific interaction of mutated cells with the embryonic retinal microenvironment may trigger the onset of retinoblastoma.(ABSTRACT TRUNCATED AT 400 WORDS)