Genetic and epigenetic regulation of human breast cancer progression and metastasis

Abstract

Breast cancer is the most common malignancy and a major cause of cancer-related deaths among women in the United States and Western Europe (American Cancer Society 1998, Wingo et al. 1998). Most women succumb to breast cancer if their tumors metastasize but cures are more likely if the cancers remain localized (Harris et al. 1992a,b,c, Walker et al. 1997). Thus, a greater understanding of the metastatic process in human breast cancer should translate into substantial improvements in therapeutic outcome for breast cancer patients. Towards that end, we will review and summarize the literature about, and begin to develop a working model for, the genetics of human breast cancer metastasis. There have been great strides in recent years with regard to our overall understanding of metastasis. Yet our apparently straightforward objective - to define cause-effect relationships for genes in breast cancer - was difficult because of four issues. First, many reports fail to distinguish between oncogenesis and progression or invasion and metastasis when reporting data. Secondly, there is a failure, by some, to recognize that breast cancer is not a single disease, but a collection of diseases. This is particularly apparent in the genetics literature. Thirdly, it is difficult to evaluate the relative importance of correlative data, particularly as it relates to mechanistic control of steps in the metastatic cascade. Fourthly, there is a tremendous noise-to-signal ratio for genetics of late-stage, metastatic breast cancers resulting from genotypic instability, phenotypic drift and tumor heterogeneity. Acknowledgements We are particularly indebted to Dr Bernard E Weissman from the University of North Carolina at Chapel Hill. Much of the published work described here was done in conjunction with his laboratory. We also appreciate the efforts of Andrea Manni, P G Satyaswaroop, Michael Verderame, and Steven Goldberg for critical reading and helpful comments and suggestions. We also appreciate the support of grants from the US Army Medical Research and Material Command (DAMD17-96-6152 to D R W); the National Foundation for Cancer Research (to D R W and L L W); PHS grant CA62168 (to D R W), the Latham Fund (L L W) and the Jake Gittlen Memorial Golf Tournament (D R W).