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Guanine nucleotide binding protein beta polypeptide: A novel transduction protein with a possible role in human breast cancer

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: Guanine nucleotide binding protein beta polypeptide 1 (GNB1) integrates signals between receptors and effector proteins and regulates certain signal transduction receptors and effectors. We have hypothesised that GNB1 is involved in the anti-apoptosis pathway mediated by mTOR, and thus may play a role in human carcinogenesis. This is the first study to examine the relationship between GNB1 mRNA expression and clinicopathological parameters. Furthermore, the correlation between GNB1 and mTORC1 was also investigated.

Methods: Specimens of breast cancer (BC) tissues (N=136) and normal tissues (N=30) underwent RNA extraction and reverse transcription. GNB1 transcript levels were determined using real-time quantitative PCR, which were correlated with clinicopathological data accrued over a 10 year follow-up period.

Results: Significantly higher mRNA transcript levels were found in the breast cancer specimens compared to normal glandular tissue in paired samples (p=0.0029 Mann-Whitney). The expression of GNB1 mRNA increased with TNM stage, and this reached statistical significance when comparing TNM1 vs. TNM2/3/4 (p=0.036 Mann-Whitney). Furthermore, the expression levels increased with increasing tumour grade (grade 2 vs. 3, p=0.006 Mann-Whitney), and with adverse patient outcomes (mortalities vs. disease free survival: 33.9 vs. 0.01, p=0.0009 Mann-Whitney). GNB1 expression was found to be higher in ductal tumours (p=0.0081 Mann-Whitney). GNB1 showed a significantly positive correlation with mTORC1 mRNA levels (r= 0.57, p < 0.000001).

Conclusions: These observations may suggest that GNB1 plays an important role in the mTORC1 related anti-apoptosis pathway and, can potentially be targeted in the treatment of human breast cancer.

Results

Conclusions

  1. We are the first group to demonstrate an association between GNB1 mRNA expression and the clinicopathological parameters of human breast cancer.
  2. Our study has shown a highly significant correlation between GNB1, Rictor and mTOR mRNA expressions using robust real time quantitative PCR methodology. Our findings in this cohort of breast cancer patients are lent greater strength by the long-term follow up of at least ten years.
  3. However several inherent limitations to our study have to be acknowledged, and can guide future avenues of research. Due to relatively small sample size, we advise due caution when interpreting our results.
  4. Further research is required into the complementary roles of GNB1 and components of the mTOR pathway in the pathogenesis of breast cancer including immunohistochemistry studies, and in vitro experiments further exploring the mechanisms involving these and other relevant molecules.
  5. Such research could guide more effective targeting of the mTOR pathway in human breast cancer, and may potentially identify further targets for therapeutic interventions.

References

  1. Jiang WG, Watkins G, Lane J, Cunnick GH, Douglas-Jones A, Mokbel K and Mansel RE: Prognostic value of rho GTPases and rho guanine nucleotide dissociation inhibitors in human breast cancers. Clin Cancer Res 9: 6432-6440, 2003.
  2. Schmidt CJ, Thomas TC, Levine MA and Neer EJ: Specificity of G protein beta and gamma subunit interactions. J Biol Chem 267: 13807-13810, 1992.
  3. Laplante M and Sabatini DM: mTOR Signaling in Growth Control and Disease. Cell 149: 274-293, 2012.

Acknowledgement

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