The adaptor protein p66Shc links membrane receptors to intracellular signalling pathways and has the potential to respond to energy status changes and regulate mitogenic signalling. Initially reported to mediate growth signals in normal and cancer cells, p66Shc has also been recognized as a pro-apoptotic protein involved in the cellular response to oxidative stress. Moreover, it is a key element in processes such as cancer cell proliferation, tumor progression, metastasis and metabolic reprogramming. Recent findings on the role of p66Shc in the above-mentioned processes have been obtained through the use of various tumor cell types, including prostate, breast, ovarian, lung, colon, skin and thyroid cancer cells. Interestingly, the impact of p66Shc on the proliferation rate was mainly observed in prostate tumors, while its impact on metastasis was mainly found in breast cancers. In this review, we summarize the current knowledge about the possible roles of p66Shc in different cancers. Keywords Cancer, cancer metabolism, p66Shc, reactive oxygen species.Eur J Clin Invest 2015; 45 (S1): 25-31The role of p66Shc in the cellular response to oxidative stress p66Shc has been extensively studied for many years, mostly in the contexts of the cellular response to oxidative stress and the mammalian lifespan. Now, p66Shc is considered to be involved in many other biological and pathological processes. p66Shc belongs to the ShcA family of adaptor proteins that consists of three members: p46Shc, p52Shc and p66Shc, with molecular masses of 46, 52 and 66 kDa, respectively. In humans, all ShcA proteins are encoded by the same gene, localized at chromosome 1q21 [1][2][3]. p66Shc, p52Shc and p46 have similar domain structures and contain three functionally identical domains (the PTB-CH1-SH2 signature): a N-terminal phosphotyrosinebinding domain (PTB), a central proline-rich domain (CH1) and a carboxy terminal Src homology 2 (SH2) domain. In response to growth factor stimuli, p66Shc is phosphorylated at the same tyrosine residues (Y293, Y240 and Y317) as the other two ShcA members (p52Shc and p46Shc) [4,5] but exerts opposite effects, acting as a negative regulator of cell proliferation [6][7][8][9]. Interestingly, p66Shc differs from p52Shc and p46Shc by the presence of an additional N-terminal proline-rich collagen homology domain (CH2), which contains a serine phosphorylation site (Ser36) that is critical for its pro-oxidant properties. Moreover, p66Shc contains a functional region (CCB, a cytochrome c-binding region) within the CH2-PTB domains that is responsible for the interaction of p66Shc with cytochrome c [10]. The intracellular localization of p66Shc remains controversial. Several reports have indicated that this cytosolic adaptor protein exhibits different subcellular localizations. At the plasma membrane, p66Shc is involved in signal transduction that mediates receptor tyrosine kinase signalling (Ras/ MAPK signalling), promotes Rac1 activation and triggers NADPH membrane oxidase reactive oxygen species (ROS) produ...