The mammalian target of rapamycin (mTOR) is a central regulator of G1 cell cycle protein synthesis that precedes commitment to normal cellular replication. We have studied the effect of cell cycle inhibitor-779 (CCI-779), a rapamycin ester that inhibits mTOR function, on the proliferation of a panel of breast cancer cell lines. Six of eight lines studied were sensitive (IC(50)< or = 50 nM) and two lines were resistant (IC(50)>1.0 microM) to CCI-779. Sensitive lines were estrogen dependent (MCF-7, BT-474, T-47D), or lacked expression of the tumor suppressor PTEN (MDA-MB-468, BT-549), and/or overexpressed the Her-2/neu oncogene (SKBR-3, BT-474). Resistant lines (MDA-MB-435, MDA-MB-231) shared none of these properties. CCI-779 (50 nM) inhibited mTOR function in both a sensitive and a resistant line. In nu/nu mouse xenografts, CCI-779 inhibited growth of MDA-MB-468 (sensitive) but not MDA-MB-435 resistant tumors. Treatment of sensitive lines with CCI-779 resulted in a decrease in D-type cyclin and c-myc levels and an increase in p27(kip-1) levels. There was good correlation between activation of the Akt pathway and sensitivity to CCI-779. Amplification of mTOR-regulated p70S6 kinase, which is downstream of Akt, may also have conferred CCI-779 sensitivity to MCF-7 cells. Taken together, the data suggest that mTOR may be a good target for breast cancer therapy, especially in tumors with Akt activation resulting from either growth factor dependency or loss of PTEN function.

This article has been cited by other articles: (Search Google Scholar for Other Citing Articles)

				D. Valmori, V. Tosello, N. E. Souleimanian, E. Godefroy, L. Scotto, Y. Wang, and M. Ayyoub Rapamycin-Mediated Enrichment of T Cells with Regulatory Activity in Stimulated CD4+ T Cell Cultures Is Not Due to the Selective Expansion of Naturally Occurring Regulatory T Cells but to the Induction of Regulatory Functions in Conventional CD4+ T Cells J. Immunol., July 15, 2006; 177(2): 944 - 949. [Abstract] [Full Text] [PDF]

				D. Del Bufalo, L. Ciuffreda, D. Trisciuoglio, M. Desideri, F. Cognetti, G. Zupi, and M. Milella Antiangiogenic Potential of the Mammalian Target of Rapamycin Inhibitor Temsirolimus Cancer Res., June 1, 2006; 66(11): 5549 - 5554. [Abstract] [Full Text] [PDF]

				J. M. Albert, K. W. Kim, C. Cao, and B. Lu Targeting the Akt/mammalian target of rapamycin pathway for radiosensitization of breast cancer Mol. Cancer Ther., May 1, 2006; 5(5): 1183 - 1189. [Abstract] [Full Text] [PDF]

				R. Namba, L. J.T. Young, C. K. Abbey, L. Kim, P. Damonte, A. D. Borowsky, J. Qi, C. G. Tepper, C. L. MacLeod, R. D. Cardiff, and J. P. Gregg Rapamycin Inhibits Growth of Premalignant and Malignant Mammary Lesions in a Mouse Model of Ductal Carcinoma In situ Clin. Cancer Res., April 15, 2006; 12(8): 2613 - 2621. [Abstract] [Full Text] [PDF]

				S. R.D. Johnston Clinical Efforts to Combine Endocrine Agents with Targeted Therapies against Epidermal Growth Factor Receptor/Human Epidermal Growth Factor Receptor 2 and Mammalian Target of Rapamycin in Breast Cancer Clin. Cancer Res., February 1, 2006; 12(3): 1061s - 1068s. [Abstract] [Full Text] [PDF]

				D. T. Teachey, D. A. Obzut, J. Cooperman, J. Fang, M. Carroll, J. K. Choi, P. J. Houghton, V. I. Brown, and S. A. Grupp The mTOR inhibitor CCI-779 induces apoptosis and inhibits growth in preclinical models of primary adult human ALL Blood, February 1, 2006; 107(3): 1149 - 1155. [Abstract] [Full Text] [PDF]

				S R D Johnston Clinical trials of intracellular signal transductions inhibitors for breast cancer -- a strategy to overcome endocrine resistance Endocr. Relat. Cancer, July 1, 2005; 12(Supplement_1): S145 - S157. [Abstract] [Full Text] [PDF]

				A. A. Adjei and M. Hidalgo Intracellular Signal Transduction Pathway Proteins As Targets for Cancer Therapy J. Clin. Oncol., August 10, 2005; 23(23): 5386 - 5403. [Abstract] [Full Text] [PDF]

				S. Chan, M. E. Scheulen, S. Johnston, K. Mross, F. Cardoso, C. Dittrich, W. Eiermann, D. Hess, R. Morant, V. Semiglazov, M. Borner, M. Salzberg, V. Ostapenko, H.-J. Illiger, D. Behringer, N. Bardy-Bouxin, J. Boni, S. Kong, M. Cincotta, and L. Moore Phase II Study of Temsirolimus (CCI-779), a Novel Inhibitor of mTOR, in Heavily Pretreated Patients With Locally Advanced or Metastatic Breast Cancer J. Clin. Oncol., August 10, 2005; 23(23): 5314 - 5322. [Abstract] [Full Text] [PDF]

				A. Boulay, J. Rudloff, J. Ye, S. Zumstein-Mecker, T. O'Reilly, D. B. Evans, S. Chen, and H. A. Lane Dual Inhibition of mTOR and Estrogen Receptor Signaling In vitro Induces Cell Death in Models of Breast Cancer Clin. Cancer Res., July 15, 2005; 11(14): 5319 - 5328. [Abstract] [Full Text] [PDF]

				F. V. Ritacco, E. I. Graziani, M. Y. Summers, T. M. Zabriskie, K. Yu, V. S. Bernan, G. T. Carter, and M. Greenstein Production of Novel Rapamycin Analogs by Precursor-Directed Biosynthesis Appl. Envir. Microbiol., April 1, 2005; 71(4): 1971 - 1976. [Abstract] [Full Text] [PDF]

				L. Wu, D. C. Birle, and I. F. Tannock Effects of the Mammalian Target of Rapamycin Inhibitor CCI-779 Used Alone or with Chemotherapy on Human Prostate Cancer Cells and Xenografts Cancer Res., April 1, 2005; 65(7): 2825 - 2831. [Abstract] [Full Text] [PDF]

				S. Vignot, S. Faivre, D. Aguirre, and E. Raymond mTOR-targeted therapy of cancer with rapamycin derivatives Ann. Onc., April 1, 2005; 16(4): 525 - 537. [Abstract] [Full Text] [PDF]

				M. Hahn, W. Li, C. Yu, M. Rahmani, P. Dent, and S. Grant Rapamycin and UCN-01 synergistically induce apoptosis in human leukemia cells through a process that is regulated by the Raf-1/MEK/ERK, Akt, and JNK signal transduction pathways Mol. Cancer Ther., March 1, 2005; 4(3): 457 - 470. [Abstract] [Full Text] [PDF]

				K. Inoki, H. Ouyang, Y. Li, and K.-L. Guan Signaling by Target of Rapamycin Proteins in Cell Growth Control Microbiol. Mol. Biol. Rev., March 1, 2005; 69(1): 79 - 100. [Abstract] [Full Text] [PDF]

				S. R. Johnston Combinations of Endocrine and Biological Agents: Present Status of Therapeutic and Presurgical Investigations Clin. Cancer Res., January 15, 2005; 11(2): 889s - 899s. [Abstract] [Full Text] [PDF]

				X. Zhou, M. Tan, V. Stone Hawthorne, K. S. Klos, K.-H. Lan, Y. Yang, W. Yang, T. L. Smith, D. Shi, and D. Yu Activation of the Akt/Mammalian Target of Rapamycin/4E-BP1 Pathway by ErbB2 Overexpression Predicts Tumor Progression in Breast Cancers Clin. Cancer Res., October 15, 2004; 10(20): 6779 - 6788. [Abstract] [Full Text] [PDF]

				J. E. Thompson and C. B. Thompson Putting the Rap on Akt J. Clin. Oncol., October 15, 2004; 22(20): 4217 - 4226. [Abstract] [Full Text] [PDF]

				J. P. Dutcher Mammalian Target of Rapamycin Inhibition Clin. Cancer Res., September 15, 2004; 10(18): 6382S - 6387S. [Abstract] [Full Text] [PDF]

				L. A. deGraffenried, L. Fulcher, W. E. Friedrichs, V. Grunwald, R. B. Ray, and M. Hidalgo Reduced PTEN expression in breast cancer cells confers susceptibility to inhibitors of the PI3 kinase/Akt pathway Ann. Onc., October 1, 2004; 15(10): 1510 - 1516. [Abstract] [Full Text] [PDF]

				C.-A. O. Nathan, N. Amirghahari, F. Abreo, X. Rong, G. Caldito, M. L. Jones, H. Zhou, M. Smith, D. Kimberly, and J. Glass Overexpressed eIF4E Is Functionally Active in Surgical Margins of Head and Neck Cancer Patients via Activation of the Akt/Mammalian Target of Rapamycin Pathway Clin. Cancer Res., September 1, 2004; 10(17): 5820 - 5827. [Abstract] [Full Text] [PDF]

				M. Hidalgo New Target, New Drug, Old Paradigm J. Clin. Oncol., June 15, 2004; 22(12): 2270 - 2272. [Full Text] [PDF]

				E. Raymond, J. Alexandre, S. Faivre, K. Vera, E. Materman, J. Boni, C. Leister, J. Korth-Bradley, A. Hanauske, and J.-P. Armand Safety and Pharmacokinetics of Escalated Doses of Weekly Intravenous Infusion of CCI-779, a Novel mTOR Inhibitor, in Patients With Cancer J. Clin. Oncol., June 15, 2004; 22(12): 2336 - 2347. [Abstract] [Full Text] [PDF]

				M. Ellis Overcoming Endocrine Therapy Resistance by Signal Transduction Inhibition Oncologist, June 3, 2004; 9(suppl_3): 20 - 26. [Abstract] [Full Text] [PDF]

				M. B. Atkins, M. Hidalgo, W. M. Stadler, T. F. Logan, J. P. Dutcher, G. R. Hudes, Y. Park, S.-H. Liou, B. Marshall, J. P. Boni, G. Dukart, and M. L. Sherman Randomized Phase II Study of Multiple Dose Levels of CCI-779, a Novel Mammalian Target of Rapamycin Kinase Inhibitor, in Patients With Advanced Refractory Renal Cell Carcinoma J. Clin. Oncol., March 1, 2004; 22(5): 909 - 918. [Abstract] [Full Text] [PDF]

				W.-C. Noh, W. H. Mondesire, J. Peng, W. Jian, H. Zhang, J. Dong, G. B. Mills, M.-C. Hung, and F. Meric-Bernstam Determinants of Rapamycin Sensitivity in Breast Cancer Cells Clin. Cancer Res., February 1, 2004; 10(3): 1013 - 1023. [Abstract] [Full Text] [PDF]

				A. Boulay, S. Zumstein-Mecker, C. Stephan, I. Beuvink, F. Zilbermann, R. Haller, S. Tobler, C. Heusser, T. O'Reilly, B. Stolz, A. Marti, G. Thomas, and H. A. Lane Antitumor Efficacy of Intermittent Treatment Schedules with the Rapamycin Derivative RAD001 Correlates with Prolonged Inactivation of Ribosomal Protein S6 Kinase 1 in Peripheral Blood Mononuclear Cells Cancer Res., January 1, 2004; 64(1): 252 - 261. [Abstract] [Full Text] [PDF]

				C. Zhou, P. A. Gehrig, Y. E. Whang, and J. F. Boggess Rapamycin Inhibits Telomerase Activity by Decreasing the hTERT mRNA Level in Endometrial Cancer Cells Mol. Cancer Ther., August 1, 2003; 2(8): 789 - 795. [Abstract] [Full Text] [PDF]

				J. M. Peralba, L. deGraffenried, W. Friedrichs, L. Fulcher, V. Grunwald, G. Weiss, and M. Hidalgo Pharmacodynamic Evaluation of CCI-779, an Inhibitor of mTOR, in Cancer Patients Clin. Cancer Res., August 1, 2003; 9(8): 2887 - 2892. [Abstract] [Full Text] [PDF]

				M. W. Harding Immunophilins, mTOR, and Pharmacodynamic Strategies for a Targeted Cancer Therapy: Commentary re: J. M. Peralba et al., Pharmacodynamic Evaluation of CCI-779, an Inhibitor of mTOR, in Cancer Patients. Clin. Cancer Res., 9: 2887-2892, 2003. Clin. Cancer Res., August 1, 2003; 9(8): 2882 - 2886. [Full Text] [PDF]

				C. J. A. Punt, J. Boni, U. Bruntsch, M. Peters, and C. Thielert Phase I and pharmacokinetic study of CCI-779, a novel cytostatic cell-cycle inhibitor, in combination with 5-fluorouracil and leucovorin in patients with advanced solid tumors Ann. Onc., June 1, 2003; 14(6): 931 - 937. [Abstract] [Full Text] [PDF]

				S. R. D. Johnston, J. Head, S. Pancholi, S. Detre, L.-A. Martin, I. E. Smith, and M. Dowsett Integration of Signal Transduction Inhibitors with Endocrine Therapy: An Approach to Overcoming Hormone Resistance in Breast Cancer Clin. Cancer Res., January 1, 2003; 9(1): 524S - 532. [Abstract] [Full Text] [PDF]

				B. K. Law, A. Chytil, N. Dumont, E. G. Hamilton, M. E. Waltner-Law, M. E. Aakre, C. Covington, and H. L. Moses Rapamycin Potentiates Transforming Growth Factor {beta}-Induced Growth Arrest in Nontransformed, Oncogene-Transformed, and Human Cancer Cells Mol. Cell. Biol., December 1, 2002; 22(23): 8184 - 8198. [Abstract] [Full Text] [PDF]

				F. Meric and K. K. Hunt Translation Initiation in Cancer: A Novel Target for Therapy Mol. Cancer Ther., September 1, 2002; 1(11): 971 - 979. [Abstract] [Full Text] [PDF]