Thirty-five percent of breast tumors show LOH at 11p15.5 indicating the presence of a tumor suppressor at this locus. We have identified a new inhibitor of cyclin-dependent kinases that maps to 11p15.5, the KIP2 gene, and propose it as a candidate for the tumor suppressor at that locus. KIP2 is expressed in the breast, and we have recently found that its expression is increased after lactation indicating a role in return to the non-proliferative state. To explore the potential role of KIP2 in breast cancer, we propose to create a mouse model for KIP2 mutations and to analyze these mice for increased incidence of cancer with special emphasis on cancer of the breast. KIP2 is genetically imprinted showing primarily maternal allele expression, and we propose to examine KIP2 imprinting the breast. We also propose to analyze the promoter of KIP2 to determine what elements control its expression in the breast. If KIP2 is a tumor suppressor, positively-acting factors controlling its expression might also be tumor suppressors and have relevance to breast cancer. Using genetic and biochemical methods, we will examine the function of conserved domains of the KIP2 protein to further understand its biochemical function in control of cell proliferation. Finally, we will search for other novel factors in the breast that may play a role in regulating Cdks. All of the experiments proposed in this grant have relevance to breast cancer either through careful examination of the biology of a strong breast-tumor suppressor candidate, KIP2, or through the search for other molecules in the breast that have the potential for regulating cell proliferation.