Centro de investigación del Cáncer - Comprehensive Cancer Center Research

Seminio CIC

9 febrero, R. Larive, CIC-IBMCC (USAL-CSIC)

Fecha: 09-02-2012 Ponente: Romain Larive, CIC-IBMCC (USAL-CSIC), lab 2

Ponencia: Role of the RRas2/TC21 GTPase in mammary gland development, breast tumorigenesis and lung metastasis

Abstract: R-Ras2/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 R-Ras2 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 R-Ras2 is not important for the development of oral squamous cell carcinoma. By contrast, we have observed that the single RRas2 gene deficiency severely impairs breast cancer tumorigenesis and the tropism of metastatic cancer cells to the lung. The characterization of the role of R-Ras2 in primary tumorigenesis indicates that this GTPase is important for the proliferation and angiogenesis of tumors. In the case of metastasis, R-Ras2 plays roles in the survival and proliferation of cancer cells within the lung parenchyma. However, this GTPase is not required for other metastatic steps of breast cancer cells, including the infiltration of lymph nodes, the intravasation, or the extravasation of cancer cells. Using a number of genetic methods, we have also discovered that R-Ras2 is important for the tumorigenesis induced by different oncoproteins in the breast (Her2, PyMT). R-Ras2 is also important for the tumorigenesis of breast cancer cells that express active mutants of the related K-Ras GTPase, indicating that R-Ras2 plays essential and non-redundant with Ras subfamily oncoproteins in this oncogenic context. Signaling experiments indicate that R-Ras2 contributes to those processes by modulating the activation of phosphatidylinositol 3-kinase alpha and downstream targets such as Akt, FoxO1/FoxO3 and S6 ribosomal protein. The analysis of the phenotype of R-Ras-deficient mice indicates that the absence of this protein is not associated to increased lethality at the embryonic or postnatal periods. R-Ras2-deficient mice also display normal growth and fertility rates. In the case of the mammary gland, we have detected however that R-Ras2 female mice display a transient delay in the mammary gland development during puberty, a physiological phase in which this gland undergoes extensive growth and morphogenesis. Taken together, these data indicate that R-Ras2 and its signaling route can be a good therapeutic target to some specific subtypes of epithelial tumors.

Lugar: Salón de Actos del CIC

Hora: 12:30

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