Abstract 2147: The RRas2/TC21 GTPase is essential for breast tumorigenesis and lung metastasis

Rras2/TC21 is a Ras superfamily GTPase with still unknown functions in vivo. Several observations suggest that this protein may be involved in tumorigenic processes. Thus, it has been shown that the expression of constitutively active RRas2 mutants leads to high levels of cell transformation in vitro. Moreover, this GTPase has been found overexpressed in a number of tumors, including lymphomas, oral and esophageal carcinoma, and breast cancer. To address the role of this protein in epithelial tumors, we have carried out an extensive characterization of this GTPase using RRas2 knockout mice and shRNA knockdown tumor cells. These studies revealed that RRas2 is not important for the development and/or malignant progression of skin and oral squamous cell carcinoma. Instead, we have observed that the RRas2 deficiency severily impairs breast cancer tumorigenesis and the tropism of metastatic cancer cells to the lung. The characterization of the role of RRas2 in primary tumorigenesis indicates that this GTPase is important for the proliferation and angiogenesis of tumors. In the case of metastasis, RRas2 is important for the survival and proliferation of cancer cells in the lung parenchyma. By contrast, this GTPase is not required for the lymph node infiltration, intravasation, or extravasation of cancer cells. Interestingly, the requirement of RRas2 is still maintained in breast cancer cells that express active mutants of K-Ras, indicating that RRas2 plays essential roles downstream of both Her2 and K-Ras. Signaling experiments indicate that RRas2 contributes to those processes by modulating the activation of phosphatidylinositol 3-kinase ≤ and downstream targets such as Akt, FoxO1/FoxO3 and S6 ribosomal protein. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2147. doi:1538-7445.AM2012-2147