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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References
Bellacosa A, de Feo D, Godwin AK, Bell DW, Cheng JQ, Altomare DA, Wan M, Dubeau L, Scambia G, Masciullo V . 1995 Int. J. Cancer 64: 280–285
Bielinski DF, Pyun NY, Linko-Stentz K, Macara I, Fine RE . 1993 Biochim. Biophys. Acta 1151: 246–256
Biscardi JS, Tice DA, Parsons SJ . 1999 Adv. Cancer Res. 76: 61–119
Bos JL, de Rooij J, Reedquist KA . 2001 Nat. Rev. Mol. Cell. Biol. 2: 369–377
Brymora A, Valova VA, Larsen MR, Roufogalis BD, Robinson PJ . 2001 J. Biol. Chem. 276: 29792–29796
Campbell RA, Bhat-Nakshatri P, Patel NM, Constantinidou D, Ali S, Nakshatri H . 2001 J. Biol. Chem. 276: 9817–9824
Caron E, Self AJ, Hall A . 2000 Curr. Biol. 10: 974–978
de Rooij J, Bos JL . 1997 Oncogene 14: 623–625
El-Ashry D, Miller DL, Kharbanda S, Lippman ME, Kern FG . 1997 Oncogene 15: 423–435
Gioanni J, Le Francois D, Zanghellini E, Mazeau C, Ettore F, Lambert JC, Schneider M, Dutrillaux B . 1990 Br. J. Cancer 62: 8–13
Goi T, Shipistin M, Lu Z, Foster DA, Klinz S, Feig LA . 2000 EMBO J. 19: 623–630
Gotoh T, Cai D, Tian X, Feig LA, Lerner A . 2000 J. Biol. Chem. 275: 30118–30123
Henry DO, Moskalenko SA, Kaur KJ, Fu M, Pestell RG, Camonis JH, White MA . 2000 Mol. Cell. Biol. 20: 8084–8092
Johnston SR . 1997 Anticancer Drugs 8: 911–930
Kasid A, Lippman ME, Papageorge AG, Lowy DR, Gelmann EP . 1985 Science 228: 725–728
Keely PJ, Rusyn EV, Cox AD, Parise LV . 1999 J. Cell Biol. 145: 1077–1088
Liu Y, el-Ashry D, Chen D, Ding IY, Kern FG . 1995 Breast Cancer Res. Treat. 34: 97–117
Marte BM, Rodriguez-Viciana P, Wennstrom S, Warne PH, Downward J . 1997 Curr. Biol. 7: 63–70
Migliaccio A, Di Domenico M, Castoria G, de Falco A, Bontempo P, Nola E, Auricchio F . 1996 EMBO J. 15: 1292–1300
Moskalenko S, Henry DO, Rosse C, Mirey G, Camonis JH, White MA . 2002 Nat. Cell Biol. 4: 66–72
Nakashima S, Morinaka K, Koyama S, Ikeda M, Kishida M, Okawa K, Iwamatsu A, Kishida S, Kikuchi A . 1999 EMBO J. 18: 3629–3642
Nakatani K, Thompson DA, Barthel A, Sakaue H, Liu W, Weigel RJ, Roth RA . 1999 J. Biol. Chem. 274: 21528–21532
Oh AS, Lorant LA, Holloway JN, Miller DL, Kern FG, El-Ashry D . 2001 Mol. Endocrinol. 15: 1344–1359
Ohtsuka T, Shimizu K, Yamamori B, Kuroda S, Takai Y . 1996 J. Biol. Chem. 271: 1253–1261
Pietras RJ, Arboleda J, Reese DM, Wongvipat N, Pegram MD, Ramos L, Gorman CM, Parker MG, Sliwkowski MX, Slamon DJ . 1995 Oncogene 10: 2435–2446
Polzin A, Shipitsin M, Goi T, Feig LA, Turner TJ . 2002 Mol. Cell Biol. 22: 1714–1722
Riese 2nd DJ, Stern DF . 1998 Bioessays 20: 41–48
Rosario M, Paterson HF, Marshall CJ . 2001 Mol. Cell Biol. 21: 3750–3762
Rusanescu G, Gotoh T, Tian X, Feig LA . 2001 Mol. Cell Biol. 21: 2650–2658
Salh B, Marotta A, Wagey R, Sayed M, Pelech S . 2002 Int. J. Cancer 98: 148–154
Scott JA, McGuire WL . 1991 Endocrine-dependent Tumors. Voight KD and Knabbe C (eds) New York: Raven Press Ltd pp 179–196
Takai Y, Sasaki T, Matozaki T . 2001 Physiol. Rev. 81: 153–208
Tian X, Rusanescu G, Hou W, Schaffhausen B, Feig LA . 2002 EMBO J. 21: 1327–1338
Turkson J, Jove R . 2000 Oncogene 19: 6613–6626
van Agthoven T, van Agthoven TL, Dekker A, van der Spek PJ, Vreede L, Dorssers LC . 1998 EMBO J. 17: 2799–2808
van Agthoven T, van Agthoven TL, Portengen H, Foekens JA, Dorssers LC . 1992 Cancer Res. 52: 5082–5088
Wang SC, Zhang L, Hortobagyi GN, Hung MC . 2001 Semin. Oncol. 28: 21–29
Wiebe VJ, Osborne CK, Fuqua SA, DeGregorio MW . 1993 Crit. Rev. Oncol. Hematol. 14: 173–188
Wolthuis RM, de Ruiter ND, Cool RH, Bos JL . 1997 EMBO J. 16: 6748–6761
Zou JX, Wang B, Kalo MS, Zisch AH, Pasquale EB, Ruoslahti E . 1999 Proc. Natl. Acad. Sci. USA 96: 13813–13818
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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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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DOI: https://doi.org/10.1038/sj.onc.1205961
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