Editors' ChoiceCancer

Unleashing the wrath of Ras

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Science Translational Medicine  04 Jan 2017:
Vol. 9, Issue 371, eaal4985
DOI: 10.1126/scitranslmed.aal4985

Abstract

Combined epigenetic silencing of two tumor suppressors promotes metastasis in luminal B breast cancers.

Despite the aggressive management of patients diagnosed with localized breast cancer, subsequent relapse and metastatic spread are not uncommon and are ultimately responsible for cancer-related deaths. Although tumor subtyping has been informative in guiding systemic therapy, fundamental questions remain regarding the mechanisms underlying tumor metastasis.

In a recent study, Olsen et al. examined the aggressive luminal B subclass of breast cancer and discovered that the RAS GTPase activating protein (RASGaP) gene DAB2IP was epigenetically silenced in nearly half of these cancers, often concomitantly with another RASGaP gene RASAL2. Co-inactivation of both DAP21P and RASAL2 was associated with advanced stage and decreased relapse-free survival in patients after local therapy. The RASGaP family of proteins functions as regulatory proteins that turn off RAS signaling by binding RAS and catalyzing RAS-GTP hydrolysis (converting RAS to its inactive form, RAS-GDP). The RAS pathway is one of the most frequently dysregulated pathways in human cancer. The loss of either of the RASGaP genes identified in the current study resulted in activation of RAS and promoted primary tumor development. The loss of both genes further enhanced RAS signaling, directly increasing breast cancer invasiveness and promoting an epithelial mesenchymal transition (EMT) phenotype and metastatic spread. Combined reconstitution of DAB2IP and RASAL2 in a metastatic in vivo model completely prevented metastasis formation. In an attempt to further elucidate mechanism, the investigators observed that loss of DAB2IP resulted in not only RAS activation but also stimulation of the nuclear factor kB (NF-κB) pathway, which was further enhanced by the dramatic activation of RAS triggered by subsequent RASAL2 loss. Both RAS and NF-κB pathways were found to play important and distinct roles in promoting the metastatic phenotype of luminal B breast cancers.

These data provide mechanistic insights on how the loss of two tumor suppressors converging upon the same biological pathways may cooperate to regulate the metastatic spread of cancer. How these observations may be translated into clinically relevant biomarkers or new therapeutic approaches will require further study. Identifying, characterizing, and inhibiting pathways responsible for metastasis are essential steps toward improving cure rates for patients.

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