Inactivation of a RASGAP Promotes Breast Cancer Progression

RAS signaling has been implicated in breast cancer progression; yet RAS mutations rarely occur in breast tumors and the mechanisms of RAS activation remain unknown. Recent studies have shown that RAS GTPase activating proteins (GAP) such as NF1, which negatively regulate RAS activity, are frequently inactivated and function as tumor suppressors in various solid tumors. McLaughlin and colleagues found that the RASGAP gene RAS protein activator-like 2 (RASAL2) was mutated in human tumors, including breast cancer, and was suppressed at the protein level in luminal breast cancer cells, indicating that RASAL2 is inactivated by both genetic and nongenetic mechanisms. RASAL2 depletion stimulated RAS activation and increased colony formation and xenograft tumor growth; the tumor-suppressive effect of RASAL2 was dependent on inhibition of HRAS and KRAS. In addition, RASAL2 loss augmented breast cancer cell migration and invasion and accelerated the formation of invasive human xenografts, suggesting that RASAL2 inactivation drives breast cancer progression. Consistent with this idea, Rasal2 deletion in a genetically engineered mouse model of luminal breast cancer enhanced the formation of metastases in the lung as well as in other organs, including the brain. Furthermore, decreased RASAL2 protein expression was detected in human breast tumors and was associated with metastasis. In particular, low levels of RASAL2 were detected in tumors of the luminal B subtype and were correlated with increased tumor recurrence and decreased overall survival in patients with luminal B tumors. Intriguingly, Rasal2 deletion also cooperated with Trp53 mutation to induce tumor formation and metastasis in a wide range of tissues found to harbor RASAL2 mutations. These results establish RASAL2 as a tumor suppressor in breast cancer and potentially other tumor types and identify RASAL2 inactivation as an alternative means to induce RAS signaling in breast cancer.

McLaughlin SK, Olsen SN, Dake B, De Raedt T, Lim E, Bronson RT, et al. The RasGAP gene, RASAL2, is a tumor and metastasis suppressor. Cancer Cell 2013;24:365–78.