The goal of Dr. Monteiro and his laboratory colleagues is to elucidate the role of genes involved in the development of breast and ovarian cancer. Their primary focus is on the function of the tumor suppressor geneBRCA1. Hereditary breast and ovarian cancers represent approximately 5% of all cases, and inherited mutations in BRCA1 account for the majority of familial breast and ovarian cancers. The human BRCA1 gene codes for a nuclear phosphoprotein that is likely to be multifunctional. Recent genetic and biochemical evidence points to the involvement of BRCA1 in two fundamental processes: DNA damage response and transcriptional regulation. The researchers' immediate goals are two-fold: to dissect the BRCA1 biochemical pathway and determine its precise biochemical function and to develop a functional assay to provide more reliable information for risk assessment in individuals carrying germline mutations in BRCA1.
In pursuit of these goals, Dr. Monteiro and his colleagues have used temperature-sensitive alleles to dissect the role of BRCA1 in DNA damage response. BRCA1 has been implicated in a variety of DNA repair processes, yet none of the evidence indicates a potential biological mechanism by which BRCA1 may act. The researchers recently discovered a cancer-predisposing allele of BRCA1 that displays temperature-sensitive (TS) activity in transcription. Utilizing their expertise in mutagenesis screening in yeast, they isolated ten additional unique TS mutants of BRCA1, which are currently being analyzed. Conditional mutants such as these are valuable research tools to dissect biochemical pathways, and Dr. Monteiro believes that these reagents will provide a direct approach to determine the precise function of BRCA1.
One of the most pressing problems in risk assessment for individuals carrying mutations in BRCA1 is the dearth of information regarding the cancer association of hundreds of missense mutations found in the population (unclassified variants). These alleles are usually very rare and, in some cases, specific to one ethnic group, making meaningful population-based studies extremelydifficult. Unless the particular mutations have been classified by case-control studies, linkage, or segregation analysis as benign polymorphisms or cancer-predisposing mutations, there is no predictive value in the diagnostics. One alternative is to devise functional assays to classify these variants. During the past 5 years, Dr. Monteiro and his colleagues have made significant progress toward development of a functional assay for BRCA1 based on its transcription activation activity. Most importantly, they have been able to validate their findings by coupling population-based data to their functional assay. Their efforts to understand the outcome of all missense mutations in BRCA1 led them to a collaborative effort to predict the outcome of these mutations in the BRCA1 C-terminus (BRCT) by using structural modeling. Because they believe that a comprehensive functional analysis will be needed to provide information for risk assessment, they are now embarking on a multicenter interdisciplinary effort to comprehensively classify BRCA1 alleles.
In summary, the strategy of Dr. Monteiro and his colleagues is to approach breast and ovarian cancer from different perspectives by studying its fundamental aspects and to develop applied methodology to rapidly translate their knowledge into useful information for patients and clinicians.