Elucidating the Role of RasGAP Genes as Tumor Suppressors in Breast Cancer

Abstract

RAS genes are commonly mutated in human cancers and aberrant Ras activation drives tumorigenesis. However, RAS mutations are rare in breast cancer, despite frequent hyperactivation of Ras and its effectors, suggesting that Ras may be activated by alternative mechanisms in this tumor type. Here I show that two RasGAP genes, RASAL2 and DAB2IP, function as important tumor and metastasis suppressors in breast cancer. Specifically, RASAL2 and DAB2IP are frequently lost in luminal tumors and suppression of these genes triggers aberrant Ras activation and drives tumor development and metastasis. Interestingly, RASAL2 and DAB2IP are specifically suppressed in luminal B tumors, a highly aggressive and metastatic subtype of luminal breast cancer. Moreover, RASAL2 and DAB2IP loss is not mutually exclusive, and a quarter of luminal B tumors have lost expression of both genes. Importantly, concomitant suppression of RASAL2 and DAB2IP occurs in the most aggressive luminal B malignancies and is associated with advanced stage and recurrence. Mechanistically, these genes cooperatively regulate two major oncogenic pathways, Ras and NF-κB, through distinct domains, and when inactivated drive the metastasis of luminal tumors in vivo. While the first RasGAP gene was identified in 1987, the precise regulation of RasGAPs remains largely unknown. Here I also present ongoing studies showing that RASAL2 and DAB2IP homo- and heterodimerize. The dimerization of Ras has only just begun to be appreciated and this finding is the first reported heterodimerization of RasGAPs. While the biological implications of RASAL2/DAB2IP dimerization are still being investigated, mutations predicted to disrupt this interaction occur in human tumors. Future studies will elucidate the importance of this interaction and should provide new fundamental insight into Ras signaling and the convergence of the Ras and NF-κB pathways. Collectively, this dissertation highlights the expanding role of RasGAP genes as tumor suppressors in human cancer. Moreover, this work reveals an alternative mechanism of Ras activation in breast cancer and provides important mechanistic insight into the pathogenesis of luminal B tumors. Lastly, the novel finding that RASAL2 and DAB2IP heterodimerize raises many exciting questions regarding RasGAP regulation and function in normal biology as well as in cancer.