The many-faced KSR1: a tumor suppressor in breast cancer

Emerging evidence supports the dual function of kinase suppressor of Ras 1 (KSR1) as an active kinase and a scaffold, although it has been extensively referred as a pseudokinase, due to the absence of key residues in its catalytic domain [1, 2]. As a scaffolding protein, KSR1 orchestrates the assembly of the protein kinases RAF, mitogen activated protein kinase (MAPK) kinase (MEK), and extracellular signal-regulated kinase (ERK) in the canonical Ras-RAF-MAPKs pathway, in a Ras-dependent manner or upon growth factor treatment [1, 3]. Conversely, structural and biochemical studies reveal that KSR1 is capable of phosphorylating MEK and more importantly, the catalytic activity of KSR is markedly increased when BRAF or inhibitor-bound CRAF is introduced in the complexes [1, 4, 5]. Such findings add complexity to the ERK spatio-temporal pathway control and identify KSR1 as a modulator of these pathways. In light of its regulatory role in oncogenic RasRAF-MAPKs signaling, extensive efforts have attempted to establish KSR1 as an oncogene in Ras-dependent cancers. Indeed, KSR1 has been shown to contribute to oncogenesis in various forms of Ras-activated cancer, including skin, pancreatic and lung carcinomas [1]. First, absence of KSR1 inhibits tumor formation in different Ras-mediated mouse models (KSR1-/-), suggesting that KSR1 is required for Ras-transduced MAPK activated tumorigenesis. Moreover, depletion of KSR1 reduces tumor growth of K-Ras-dependent pancreatic and lung cancer xenografts in nude mice, further supporting KSR1 as an oncogene as well as a potential therapeutic target. However, our own studies reveal an interesting, and yet unexpected role of KSR1 in breast cancer, where Ras mutations are rare. Using tumor tissue microarrays in a large patient cohort with a long term follow-up, we observe that breast cancer patients with high KSR1 had better disease freeand overall survival, results also supported by Oncomine analyses, microarray data and genomic data from paired tumor and cell-free DNA (cfDNA) samples revealing loss of heterozygosity [6]. KSR1 expression is positively associated with breast cancer 1, early onset (BRCA1), BRCA1-associated ring domain 1 (BARD1) and checkpoint kinase 1 (Chk1) levels in breast cancer specimens. Intriguingly, phospho-profiling of major components of the canonical Ras-RAF-MAPKs pathway, including RAF, MEK and ERK, show no significant changes upon KSR1 overexpression or depletion. These results underline its role beyond coordinating MAPKs signaling and challenge its oncogenic function in breast cancer. Further experiments support a tumor suppressive Editorial