Determinants of Rapamycin Sensitivity in Breast Cancer Cells

Woo Chul Noh, Wallace H. Mondesire, Junying Peng, Weiguo Jian, Haixia Zhang, Jin Jiang Dong, Gordon Mills, Mien Chie Hung, Funda Meric-Bernstam

Research output: Contribution to journalArticle

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Abstract

Purpose: Rapamycin inhibits the serine-threonine kinase mammalian target of rapamycin (mTOR), blocking phosphorylation of p70 S6 kinase (S6K1) and 4E-binding protein 1 (4E-BP1) and inhibiting protein translation and cell cycle progression. Rapamycin and its analogues are currently being tested in clinical trials as novel-targeted anticancer agents. Although rapamycin analogues show activity in clinical trials, only some of the treated patients respond. The purpose of this study is to identify determinants of rapamycin sensitivity that may assist the selection of appropriate patients for therapy. Experimental Design: Breast cancer cell lines representing a spectrum of aberrations in the mTOR signaling pathway were tested for rapamycin sensitivity. The expression and phosphorylation state of multiple components of the pathway were tested by Western blot analysis, in the presence and absence of rapamycin. Results: Cell proliferation was significantly inhibited in response to rapamycin in 12 of 15 breast cancer cell lines. The ratio of total protein levels of 4E-BP1 to its binding partner eukaryotic initiation factor 4E did not predict rapamycin sensitivity. In contrast, overexpression of S6K1, and phosphorylated Akt independent of phosphatase and tensin homologue deleted from chromosome 10 status, were associated with rapamycin sensitivity. Targeting S6K1 and Akt with small interfering RNA and dominant-negative constructs, respectively, decreased rapamycin sensitivity. Rapamycin inhibited the phosphorylation of S6K1, ribosomal S6 protein, and 4E-BP1 in rapamycin-resistant as well as -sensitive cells, indicating that its ability to inhibit the mTOR pathway is not sufficient to confer sensitivity to rapamycin. In contrast, rapamycin treatment was associated with decreased cyclin D1 levels in the rapamycin-sensitive cells but not in rapamycin-resistant cells. Conclusions: Overexpression of S6K1 and expression of phosphorylated Akt should be evaluated as predictors of rapamycin sensitivity in breast cancer patients. Furthermore, changes in cyclin D1 levels provide a potential pharmacodynamic marker of response to rapamycin.

Original languageEnglish (US)
Pages (from-to)1013-1023
Number of pages11
JournalClinical Cancer Research
Volume10
Issue number3
DOIs
StatePublished - Feb 1 2004
Externally publishedYes

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Sirolimus
Breast Neoplasms
Carrier Proteins
Cyclin D1
Phosphorylation
Eukaryotic Initiation Factor-4E
Clinical Trials
70-kDa Ribosomal Protein S6 Kinases
S 6
Cell Line
Chromosomes, Human, Pair 10
Protein-Serine-Threonine Kinases

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Noh, W. C., Mondesire, W. H., Peng, J., Jian, W., Zhang, H., Dong, J. J., ... Meric-Bernstam, F. (2004). Determinants of Rapamycin Sensitivity in Breast Cancer Cells. Clinical Cancer Research, 10(3), 1013-1023. https://doi.org/10.1158/1078-0432.CCR-03-0043

Determinants of Rapamycin Sensitivity in Breast Cancer Cells. / Noh, Woo Chul; Mondesire, Wallace H.; Peng, Junying; Jian, Weiguo; Zhang, Haixia; Dong, Jin Jiang; Mills, Gordon; Hung, Mien Chie; Meric-Bernstam, Funda.

In: Clinical Cancer Research, Vol. 10, No. 3, 01.02.2004, p. 1013-1023.

Research output: Contribution to journalArticle

Noh, WC, Mondesire, WH, Peng, J, Jian, W, Zhang, H, Dong, JJ, Mills, G, Hung, MC & Meric-Bernstam, F 2004, 'Determinants of Rapamycin Sensitivity in Breast Cancer Cells', Clinical Cancer Research, vol. 10, no. 3, pp. 1013-1023. https://doi.org/10.1158/1078-0432.CCR-03-0043
Noh WC, Mondesire WH, Peng J, Jian W, Zhang H, Dong JJ et al. Determinants of Rapamycin Sensitivity in Breast Cancer Cells. Clinical Cancer Research. 2004 Feb 1;10(3):1013-1023. https://doi.org/10.1158/1078-0432.CCR-03-0043
Noh, Woo Chul ; Mondesire, Wallace H. ; Peng, Junying ; Jian, Weiguo ; Zhang, Haixia ; Dong, Jin Jiang ; Mills, Gordon ; Hung, Mien Chie ; Meric-Bernstam, Funda. / Determinants of Rapamycin Sensitivity in Breast Cancer Cells. In: Clinical Cancer Research. 2004 ; Vol. 10, No. 3. pp. 1013-1023.
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