SIRT1 is a hub in a large scale-free network of proteins. A relatively scant amount of clinical data has suggested an oncogenic role for SIRT1 in breast cancer, however many breast cancer cell lines have lost Sirt1 alleles or contain mutations in the Sirt1 gene, suggesting a role as a non-classical tumor suppressor. Recently, we showed that the absence of SIRT1 catalytic activity neither suppressed nor promoted breast tumor formation and progression in mice carrying the MMTV-PyMT transgene. These highly variable observations suggest that the molecular, physiological and environmental contexts are critical in defining the role of SIRT1 in cancer. We set out to determine whether dietary modulators of SIRT1 activity, high fat diet and resveratrol, could influence tumorigenesis in mice with normal or mutant Sirt1 genes. We Epimedoside-A report below that both dietary modifications modestly affected the onset of tumorigenesis but were not dependent on SIRT1 activity. The role of SIRT1 in cancer is the subject of controversy. The abundance or activity of SIRT1 has been reported to decrease or increase in tissues following treatment with HFD or resveratrol respectively, so we set out to determine if the tumor promoting or inhibiting effects of these treatments on oncogenesis is dependent on SIRT1. The two treatments had bigger effects on tumorigenesis in mice with compromised SIRT1 activity. The parsimonious inference from these results is that neither HFD nor resveratrol affect tumorigenesis by modulating SIRT1 function. This conclusion is consistent with our previous work showing that development of skin tumors, intestinal tumors, and mammary tumors in mice is not influenced by SIRT1 catalytic activity. Obesity increases the risk of development and foreshortens survival in numerous cancer types, Mepiroxol including breast cancer. A diet high in fat is known to accelerate tumor development in mice carrying the MMTV-PyMT transgene. Mammary carcinogenesis is dependent on estrogen in the MMTV-PyMT transgenic mice and resveratrol has estrogenic properties in mammary tumor cells. Indeed, mammary tumor promotion by resveratrol has been reported. SIRT1 plays a modulating role in signalling by the estrogen receptor, with evidence pointing to the possibility of both a suppressive or enhancing effect. The effects of estrogen receptor activation are dependent on the dosage of its cognate gene suggesting that the tumor promotion seen with resveratrol in Sirt1Y animals may be a result of SIRT1 dosagedependent modulation of estrogen receptor signalling. An analogous dose-dependent effect of SIRT1 on UV-induced skin carcinogenesis has been reported. Conversely, this result may point to SIRT1-independent effects of resveratrol as have been reported. Resveratrol has a number of established cellular target proteins such as the mitochondrial ATP synthase, quinone reductase 2, and the estrogen receptor. The TRPM2 channel belongs to the melastatin subfamily of the mammalian transient receptor potential channels, which share several conserved domains with other TRPM channels, such as the TRPM homology domains in the Nterminus and the TRP box and coiled-coil domain in the Cterminus. The TRPM2 channel is a homo-tetramer and each subunit contains six transmembrane segments with a poreforming region between the fifth and sixth segments and intracellular N- and C-termini. The TRPM2 channel is a non-selective cation channel and permeates calcium ion, and is activated by intracellular ADP-ribose or intracellular calcium. Accumulating evidence indicates that the TRPM2 channel plays an important role in a number of physiological and pathophysiological processes, including neurodegeneration, immunological functions, insulin release.