The main hypothesis of this project was that breast cancer cells utilize various alternative mechanisms to circumvent a major restriction point in the G1 phase of cell cycle progression. Furthermore, we speculated that the sum of the various subsets of tumors with abnormalities in either player of the cell cycle inhibitor p16 pathway, accounts for a very significant number of breast cancers. It was a main objective of this research project to elucidate the overall extent of pl6 involvement in the tumorigenesis of the breast. An additional major goal was to evaluate whether p16 fulfills all the criteria to be considered a senescence control gene. In the course of these studies we determined that 1) Abnormalities affecting the INK4A locus are common in breast cancer; 2) Disregulation of expression of the genes encoded by such locus (pl6 and p14ARF) affects most breast carcinomas. Overexpression of p16 associates with more aggressive breast cancer frequently, while many other breast carcinomas show loss of p16 expressing; and 3) p16 inactivation is a key necessary event that HMEC use to achieve extended life in vitro and to overcome the MO senescence arrest.