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Contrasting correlations of mTORC1 and Rictor with clinicopathological parameters in human breast cancer: A ‘Gas and Pedal’ relationship?

U. Wazir1, 2, A. Kasem2, W. G. Jiang3, A. K. Sharma1 and K. Mokbel1, 2

1 The London Breast Institute, Princess Grace Hospital, London, UK;
2 Department of Breast Surgery, St. George’s Hospital and Medical School, University of London, London, U.K;
3 Metastasis & Angiogenesis Research Group, University Department of Surgery, Cardiff University School of Medicine, Cardiff University, Heath Park, Cardiff, Wales, UK.

Abstract

Introduction: mTOR (the mammalian target of rapamycin) plays a key role in regulation of cellular metabolism, growth, and proliferation. It forms two multi-protein complexes known as complex 1 (mTORC1) and 2 (mTORC2), whose respective core proteins are Raptor and Rictor. This study examines the relationship between mRNA expression of mTORC1 and Rictor in human breast cancer and clinicopathological parameters.

Methods: Specimens of breast cancer (BC) tissues (N=150) and normal tissues (N=31) underwent RNA extraction and reverse transcription. mTORC1 transcript levels determined using real-time quantitative PCR were analysed against clinicopathological data accrued over a 10 year follow-up period.

Results: Higher mRNA transcript levels of mTORC1 were found in the breast cancer specimens compared to normal tissue (p=0.0018, twosample t), in increased NPI (53 for NPI1 vs. 219 for NPI3), in higher tumour grades (37 for grade 2 vs. 159 for grade 3, p=0.047, twosample t), and in ductal tumours (p=0.0014, two-sample t). Higher expression levels were associated with worse overall survival (p=0.01, Wilcoxon). In contrast, higher levels of Rictor mRNA expression were found in normal breast tissue, lower NPI stage (NPI1 vs. 2: p= 0.03, Mann-Whitney) and lower tumour grade (grade 1 vs. grade 3: p=0.01, Mann-Whitney). Patients with higher Rictor expression had a significantly better overall (p=0.037, Wilcoxon) and disease-free (p=0.048, Wilcoxon) survival.

Conclusions: These observations are consistent with mTORC1 role in the anti-apoptosis pathway and suggest that selective inhibitors of mTORC1 are likely to be a more effective therapeutic strategy than dual mTOR inhibitors in human breast cancer.

Results

Conclusions

  1. Our study has shown significant correlations between the expression of mTORC1 and parameters of advanced disease in breast carcinogenesis, including tumour grade and NPI and an inverse relationship to overall survival.
  2. This reiterates the potential for a therapeutic role for rapalogues in breast cancer.
  3. The correlation of mTORC1 expression with ductal carcinoma identifies a possible parameter for identification of potential rapamycin sensitive patients, as does the correlation with hTERT expression.
  4. This is the first study to show an inverse relationship between the Rictor subunit of mTORC2, NPI and tumour grade, as well as demonstrate a significant direct correlation of Rictor expression with disease-free and overall survival.
  5. This is suggestive of more extensive countervailing role of mTORC2 verses mTORC1 than previously postulated, potentially resembling a 'gas and pedal' model.

References

  1. Laplante M and Sabatini DM: mTOR Signaling in Growth Control and Disease. Cell 149: 274-293, 2012.
  2. Noh WC, Mondesire WH, Peng J, et al: Determinants of rapamycin sensitivity in breast cancer cells. Clin Cancer Res 10: 1013-1023, 2004.
  3. Sarbassov DD, Ali SM, Kim DH, et al: Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 14: 1296-1302, 2004.

Acknowledgement

This study was funded by grants from the Breast Cancer Hope Foundation (London, UK).