Noxa increases the size of the G1/G0-phase cell population and decreases that of the Sphase population, suggesting that Noxa expression is required for S-phase entry in unstressed cells. To strengthen the significance of these findings, we have eliminated the likelihood of either mutations occurring within the NOXA gene, or alternatively spliced NOXA gene products contributing to the proproliferative functions of Noxa reported here. Our results showing that Noxa expression is required for S-phase entry in breast cancer cells are further supported by data from another study which showed that Noxa expression is induced during the S-phase in actively dividing B cells. Furthermore, enhanced Noxa expression was associated with prostate cancer progression in a recent report, and high expression of Noxa has also been observed in chronic lymphocytic leukemia cells, suggesting that Noxa likely plays a role in highly proliferating cells of various tissue types. While additional studies are needed to elucidate the mechanisms by which Noxa promotes E2-induced cell cycle progression, it is reasonable to speculate the involvement of phosphorylation of Noxa at serine 13, since it has been shown that glucose-dependent phosphorylation of Noxa at serine 13 promotes cell growth via preferential channeling of glucose to the pentose phosphate pathway. An intriguing question is whether a link between estrogen signaling and glucose metabolism exists, which would favor an anabolic state that is conducive to cellular proliferation. Notably, E2-dependent upregulation of Noxa on its own did not induce apoptosis in our cell culture model under normal, unstressed conditions. Dependent upon cell type and the context of cellular stimuli. For example, when wild type mouse embryonic fibroblasts that had been transduced with E1A, MYC, and H-RASG12V oncogenes were subjected to RNA interference to downregulate endogenous Noxa, they were protected from p53- dependent apoptosis, supporting a proapoptotic role for Noxa under these conditions. On the other hand, hematopoietic cells from NOXA knockout mice were normally sensitive to apoptosis induction, suggesting that Noxa was dispensable for apoptosis in this context. Collectively, these lines of evidence indicate that Noxa’s pro-apoptotic function is highly regulated and GDC-0449 molecular weight cell-type specific. Since cell cycle regulation and apoptosis are closely linked cellular processes, future studies should focus on identifying the cellular signals that differentially activate the proproliferative and proapoptotic functions of Noxa. To conclude, in addition to the already well-documented proapoptotic function of Noxa, we herein identify a novel role for Noxa as a positive regulator of cell cycle progression in ERpositive breast cancer cells. Our studies suggest that these dual functions of Noxa could have important clinical implications, especially in ER-positive breast cancer patients and in cases where chemotherapeutic and hormonal-therapy drugs, which modulate Noxa expression, are administered. Presumably, in coordination with other proteins, Noxa could participate in balancing cell survival and cell death in a stimuli- and cell-context-dependent manner. Our data suggest that a more detailed understanding of Noxa’s many roles as a regulator of diverse cellular functions is required in order to ascertai.