The biological processes that unfold during the G1-phase of the cell cycle are dependent on extracellular mitogenic factors that signal the cell to enter a state of quiescence, or commit to a cell-cycle round by passing the restriction point (R-point) and enter the S-phase. Unlike normal cells, cancer cells evolved the ability to evade the R-point and continue through the cell cycle even in the presence of extensive DNA damage or absence of mitogenic signals. The purpose of this study was to perform a quantitative proteomic evaluation of the biological processes that are responsible for driving MCF-7 breast cancer cells into division even when molecular checkpoints such as the G1/S R-point are in place. Nuclear and cytoplasmic fractions of the G1 and S cell-cycle phases were analyzed by LC-MS/MS to result in the confident identification of more than 2700 proteins. Statistical evaluation of the normalized data resulted in the selection of proteins that displayed twofold or more change in spectral counts in each cell state. Pathway mapping, functional annotation clustering, and protein interaction network analysis revealed that the top-scoring clusters that could play a role in overriding the G1/S transition point included DNA damage response, chromatin remodeling, transcription/translation regulation, and signaling proteins.