Involvement of R-Ras and Ral GTPases in estrogen-independent proliferation of breast cancer cells.
A key step in the progression of breast cancer is the conversion of cells from an estrogen-dependent to an estrogen-independent state. Yet the molecular mechanisms underlying this transition in the control of cell proliferation of breast cancer cells remain poorly understood. A potential role for Ras-related GTPases in this process was suggested by the finding that BCAR3/AND-34, a protein isolated on the basis of its ability to convert MCF-7 and ZR-75 breast cancer cell lines to estrogen independence and tamoxifen resistance, is a guanine nucleotide exchange factor with the potential to activate the Ras-related Ral, R-Ras and Rap GTPases. In this study we investigated the potential contribution of these GTPases to the generation of estrogen-independence in MCF-7 cells. We found that elevated R-Ras but not Ral or Rap activity was sufficient to induce estrogen-independent proliferation of MCF-7 cells. The effect of R-Ras was dependent upon its ability to constitutively activate the AKT kinase. Interestingly, although AKT was also constitutively activated when estrogen-independent proliferation was induced by over-expression of EGF receptors, this mechanism of hormone independence did not require AKT activation. In contrast, EGF receptors did require Ral activation to induce estrogen-independent proliferation, while Ral activation was not required for estrogen-induced proliferation of MCF-7 cells. These findings suggest that Ral activity takes on a significant role in controlling cell proliferation of breast cancer cells when progression to estrogen-independence is associated with over-expression of EGF receptor family members. Moreover, because R-Ras promotes hormone-independent growth in a manner distinct from EGF receptors, it may participate in the conversion of breast cancer cells to estrogen independence when over-expression of EGF receptor family members is not involved.
Yu
Yi
Y
Department of Biochemistry, Tufts University School of Medicine, Boston, Massachusetts, MA 02111, USA.
Feig
Larry A
LA
D015153:Blotting, Western; D001943:Breast Neoplasms / Q000473:pathology*; D002455:Cell Division / Q000502:physiology*; D066246:ErbB Receptors / Q000235:genetics; D004967:Estrogens / Q000502:physiology*; D020558:GTP Phosphohydrolases / Q000502:physiology*; D006801:Humans; D014407:Tumor Cells, Cultured; D020725:ral GTP-Binding Proteins / Q000502:physiology*; D018631:ras Proteins / Q000502:physiology*
D004967:Estrogens; D066246:ErbB Receptors; D020558:GTP Phosphohydrolases; C085929:RRAS protein, human; D020725:ral GTP-Binding Proteins; D018631:ras Proteins