Breast Cancer Research and Treatment

, Volume 110, Issue 3, pp 477–483

Activation of the mTOR signaling pathway in breast cancer and its correlation with the clinicopathologic variables

  • Woo Chul Noh
  • Yang Hee Kim
  • Min Suk Kim
  • Jae Soo Koh
  • Hyun-Ah Kim
  • Nan Mo Moon
  • Nam-Sun Paik
Preclinical Study

Abstract

Aims

Rapamycin and its analogues are currently being tested in clinical trials as novel–targeted anticancer agents. Pre-clinical studies that used breast cancer cell lines have suggested that p-Akt or p-S6K1 expressing tumors, as well as PTEN negative tumors, were sensitive to rapamycin. The aims of this study were to determine the proportion of breast cancer that could be candidates for rapamycin treatment and to elucidate the clinicopathologic characteristics and prognosis of potentially rapamycin-sensitive tumors.

Methods

We evaluated the expressions of PTEN, p-Akt and p-S6K1 by performing immunohistochemistry in 122 breast cancer tissues. We analyzed the association of the expression of these proteins with the cliniopathologic variables and the disease-free survival.

Results

PTEN negative tumors, p-Akt expressing tumors and p-S6K1 expressing tumors constituted 4.1% (5/122), 41.0% (50/122), and 36.1% (44/122) of the total tumors, respectively. The proportion of tumors that met the criteria of rapamycin sensitivity was 54.9% (67/122). We could not find any significant correlation between the expression of these proteins and the other prognostic factors. However, the prognosis of tumors with a p-S6K1 expression was significantly worse than that of the p-S6K1 negative tumors.

Conclusion

Based on the status of the PTEN, p-Akt and p-S6K1 expressions as predictors of rapamycin sensitivity, this study suggested that over 50% of breast cancer patients could be potential candidates for rapamycin treatment. In addition, the p-S6K1 expression may constitute an independent prognostic factor for disease-free survival.

Keywords

Breast cancer mTOR Phosphorylated Akt Phosphorylated S6 kinase Prognostic factor PTEN Rapamycin 

References

  1. 1.
    Vignot S, Faivere S, Aguirre D, Raymond E (2005) mTOR-targeted therapy of cancer with rapamycin derivatives. Ann Oncol 16:525–537PubMedCrossRefGoogle Scholar
  2. 2.
    Rowinsky EK (2004) Targeting the molecular target of rapamycin (mTOR). Curr Opin Oncol 16:564–575PubMedCrossRefGoogle Scholar
  3. 3.
    Noh WC, Paik NS (2003) Translational regulation: a novel target for breast cancer therapy. J Korean Breast Cancer Soc 6:8–14Google Scholar
  4. 4.
    Morgensztern D, McLeod HL (2005) PI3K/Akt/mTOR pathway as a target for cancer therapy. Anti-Cancer Drug 16:797–803CrossRefGoogle Scholar
  5. 5.
    Carraway H, Hidalgo M (2004) New target for therapy in breast cancer: mammalian target of rapamycin (mTOR) antagonists. Breast Cancer Res 6:219–224PubMedCrossRefGoogle Scholar
  6. 6.
    Garber K (2001) Rapamycin’s resurrection: a new way to target the cancer cell cycle. J Natl Cancer Inst 93:1517–1519PubMedCrossRefGoogle Scholar
  7. 7.
    Raymond E, Alexandre J, Faivre S et al (2004) Safety and pharmacokinetics of escalated doses of weekly intravenous infusion of CCI-779, a novel mTOR inhibitor, in patients with cancer. J Clin Oncol 22:2336–2347PubMedCrossRefGoogle Scholar
  8. 8.
    O’Donnell M, Faivre I, Judson C et al (2003) A phase I study of oral mTOR inhibitor RAD 001 as monotherapy to identify the optimal biologically effective dose using toxicity, pharmacokinetic and pharmacodynamic endpoints in patients with solid tumors. Proc Am Soc Clin Oncol 22:200Google Scholar
  9. 9.
    Chan S, Scheulen ME, Johston S et al (2005) 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 23:5314–5322PubMedCrossRefGoogle Scholar
  10. 10.
    DeGraffenried LA, Friedrichs WE, Russel DH et al (2004) Inhibition of mTOR activity restores tamoxifen response in breast cancer cells with aberrant Akt activity. Clin Cancer Res 10:8059–8067PubMedCrossRefGoogle Scholar
  11. 11.
    Osborne CK, Shou J, Massarweh S et al (2005) Crosstalk between estrogen receptor and growth factor receptor pathway as a cause for endocrine therapy resistance in breast cancer. Clin Cancer Res 11:865s–870sPubMedGoogle Scholar
  12. 12.
    Chow LWC, Sun Y, Jassem J et al (2006) Phase 3 study of temsirolimus with letrozole or letrozole alone in postmenopausal women with locally advanced or metastatic breast cancer. Paper presented at the 29th Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 2006Google Scholar
  13. 13.
    Noh WC, Mondesire WH, Peng J et al (2004) Determinants of rapamycin sensitivity in breast cancer cells. Clin Cancer Res 10:1013–1023PubMedCrossRefGoogle Scholar
  14. 14.
    Yu K, Toral-Barza L, Discafani C et al (2001) mTOR, a novel target in breast cancer: the effect of CCI-779, an mTOR inhibitor, in preclinical models of breast cancer. Endocr Relat Cancer 8:249–258PubMedCrossRefGoogle Scholar
  15. 15.
    Allred D, Bustamante M, Daniel C et al (1990) Immunohistochemical analysis of estrogen receptors in human breast carcinomas. Arch Surg 125:107–116PubMedGoogle Scholar
  16. 16.
    Xu G, Zhang W, Bertram P, Zheng X et al (2004) Pharmacogenomic profiling of PI3K/PTEN-Akt-mTOR pathway in common breast tumors. Int J Oncol 24:893–900PubMedGoogle Scholar
  17. 17.
    Mills GB, Lu Y, Fang X et al (2001) The role of genetic abnormalities of PTEN and the phosphatidylinositol 3-kinase pathway in breast and ovarian tumorigenesis, prognosis, and therapy. Semin Oncol 28:125–141PubMedCrossRefGoogle Scholar
  18. 18.
    Nelen MR, van Staveren WC, Peeters E et al (1997) Germline mutation in the PTEN/MMAC-1 gene in patients with Cowden disease. Human Mol Genet 6:1384–1387Google Scholar
  19. 19.
    Rhei E, Kang L, Bogomolniy F et al (1997) Mutation analysis of putative tumor suppressor gene PTEN/MMAC-1 in primary breast carcinomas. Cancer Res 57:3657–3659PubMedGoogle Scholar
  20. 20.
    Li J, Yen C, Liaw D et al (1997) PTEN, a putative protein tyrosine phosphatase gene mutated in brain, breast, and prostate cancer. Science 275:1943–1947PubMedCrossRefGoogle Scholar
  21. 21.
    Nicholson KM, Anderson NG (2002) The protein kinase B/Akt signaling pathway in human malignancy. Cell Signal 14:381–395PubMedCrossRefGoogle Scholar
  22. 22.
    Meric F, Hung MC, Hortobagyi GN et al (2002) HER2/neu in management of invasive breast cancer. J Am Coll Surg 194:488–501PubMedCrossRefGoogle Scholar
  23. 23.
    Zhou X, Tan M, Hawthorne VS et al (2004) Activation of the Akt/mammalian target of rapamycin/4E-BP1 pathway by erbB-2 overexpression predicts tumor progression in breast cancers. Clin Cancer Res 15:6779–6788CrossRefGoogle Scholar
  24. 24.
    Tokunaga E, Kataoka A, Kimura Y et al (2006) The association between Akt activation and resistance to hormone therapy in metastatic breast cancer. Eur J Cancer 42:629–635PubMedCrossRefGoogle Scholar
  25. 25.
    Schmitz KJ, Otterbach F, Callies R et al (2004) Prognostic relevance of activated Akt kinase in node negative breast cancer: a clinicopathologic study of 99 cases. Modern Pathol 17:15–21CrossRefGoogle Scholar
  26. 26.
    Barlund M, Forozan F, Kononen J et al (2000) Detecting activation of ribosomal protein S6 kinase by complementary DNA and tissue microarray analysis. J Natl Cancer Inst 92:1252–1259PubMedCrossRefGoogle Scholar
  27. 27.
    Hage JA, Broek LJCM, Legrand C et al (2004) Overexpression of P70 S6 kinase protein is associated with risk of locoregional recurrence in node-negative premenopausal early breast cancer patients. Br J Cancer 90:1543–1550PubMedCrossRefGoogle Scholar
  28. 28.
    Peralba JM, DeGraffenried LA, Friedrichs WE et al (2003) Phamacodynamic evaluation of CCI-779, an inhibitor of mTOR, in cancer patients. Clin Cancer Res 9:2887–2892PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Woo Chul Noh
    • 1
  • Yang Hee Kim
    • 2
  • Min Suk Kim
    • 3
  • Jae Soo Koh
    • 3
  • Hyun-Ah Kim
    • 1
  • Nan Mo Moon
    • 1
  • Nam-Sun Paik
    • 1
  1. 1.Department of SurgeryKorea Cancer Center HospitalSeoulKorea
  2. 2.Department of SurgeryKangwon National University, College of MedicineChuncheonKorea
  3. 3.Department of PathologyKorea Cancer Center HospitalSeoulKorea

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