Evidence for downregulation of the negative regulator SPRED2 in clinical prostate cancer

Enhanced intracellular signalling is an important mechanism contributing to cancer progression (Brognard et al, 2011). Intracellular signalling is normally subject to constitutive levels of regulation that modulate the level of intracellular signalling (Murphy et al, 2010). Negative regulators provide a feedback mechanism that controls the intensity and duration of exogenous stimulation and have been particularly implicated in modulation of the MAPK pathway. Key members of this group, including the MAPK phosphatases, RKIP1, SPROUTY and SEF, have been consistently reported to be downregulated in many malignancies, including prostate cancer (Murphy et al, 2010). The SPROUTY-related enabled/vasodilator-stimulated phosphoprotein homology 1 domain-containing (SPRED) proteins (SPRED1 and 2) were first described by Wakioka et al (2001). SPREDs function by forming a complex with Raf and inhibiting activation of MEK (Wakioka et al, 2001; Bundschu et al, 2007). To date, there is very limited data on expression levels of SPRED1 and 2 in human cancers. SPREDs have only been investigated in hepatocellular carcinoma, with an observed downregulation of SPRED1 and 2 (Yoshida et al, 2006). Decreased SPRED levels were also associated with increased tumour invasion and metastasis (Yoshida et al, 2006; Ma et al, 2011). Given known patterns of loss of other signalling regulators in prostate cancer, we investigated whether expression of SPREDs was similarly altered.