Genetic strategies of tumor suppression. The evaluation of the cancer cell is a complex multigene process. Tumor suppressor genes that are lost or inactivated, as well as genes that are overexpressed, play key roles in tumor progression. The identification of overexpressed genes has been expedited by the presence of transforming genes in some animal retroviruses. However, tumor suppressor genes have been difficult to identify and isolate because of their loss or inactivation during tumorigenesis. By a variety of methods, summarized in this review, a few tumor suppressors have been cloned and characterized, and many more have been recognized indirectly. The general finding at this time is that the same tumor suppressors (and oncogenes) are found associated with many different tumors, that several different altered genes are found typically in the same tumors, and that other oncogenes and tumor suppressor genes seem to be characteristically altered in particular tumor types as well. Functions of tumor suppressor genes include the control of normal cell activities such as proliferation and differentiation as well as senescence, which is a special kind of differentiation in which cells lose their ability to divide. The genetic basis of senescence and identification of genes involved in overcoming senescence, leading to immortalization (i.e., indefinite growth potential), are important areas of current investigation. Our laboratory is engaged in senescence/immortalization studies as a result of our discovery that normal human mammary epithelial cells can be immortalized by DNA of the human papilloma virus. These new studies are summarized here. 