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Involvement of R-Ras and Ral GTPases in estrogen-independent proliferation of breast cancer cells

Oncogene volume 21, pages 7557–7568 (2002)Cite this article

Abstract

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.

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Acknowledgements

We thank Dr Vimla Band for helpful suggestions during the course of this project. This work was funded by grant #RO1CA47391 from the NCI to LA Feig and postdoctoral fellowships to Y Yu from the Canadian Institutes of Health Research and Susan B Komen Breast Cancer Foundation.

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  1. Department of Biochemistry, Tufts University School of Medicine, Boston, 02111, Massachusetts, MA, USA

    Yi Yu & Larry A Feig

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Correspondence to Larry A Feig.

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Yu, Y., Feig, L. Involvement of R-Ras and Ral GTPases in estrogen-independent proliferation of breast cancer cells. Oncogene 21, 7557–7568 (2002). https://doi.org/10.1038/sj.onc.1205961

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