Prognostic and therapeutic implications of mTORC1 and Rictor expression in human breast cancer

Wazir,U.; Newbold,R. F.; Jiang,W. G.; Sharma,A. K.; Mokbel,K.

doi:10.3892/or.2013.2346

Prognostic and therapeutic implications of mTORC1 and Rictor expression in human breast cancer

Authors:
- U. Wazir
- R. F. Newbold
- W. G. Jiang
- A. K. Sharma
- K. Mokbel
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Affiliations: The London Breast Institute, Princess Grace Hospital, London, UK, Brunel Institute of Cancer Genetics and Pharmacogenomics, Faculty of Life Sciences, Brunel University, Uxbridge, London, UK, Metastasis and Angiogenesis Research Group, University Department of Surgery, Cardiff University School of Medicine, Cardiff University, Cardiff, Wales, UK
Published online on: March 13, 2013 https://doi.org/10.3892/or.2013.2346
Pages: 1969-1974

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Abstract

The mammalian target of rapamycin (mTOR) plays a key role in the regulation of cellular metabolism, growth and proliferation. It forms two multi-protein complexes known as complex 1 (mTORC1) and 2 (mTORC2). Raptor and Rictor are the core proteins for mTORC1 and mTORC2, respectively. This study examines the relationship between mTORC1, Rictor and Raptor mRNA expression and human breast cancer. Furthermore, the correlation between mTORC1 and hTERT was investigated. Breast cancer tissues (n=150) and normal tissues (n=31) were analysed using reverse transcription and quantitative PCR. Transcript levels were correlated with clinicopathological data. Higher mTOR expression was noted in breast cancer tissue (P=0.0018), higher grade tumours (grade 2 vs. 3, P=0.047), in ductal tumours (P=0.0014), and was associated with worse overall survival (P=0.01). Rictor expression was significantly higher in background breast tissues compared with tumours and was inversely related to the Nottingham Prognostic Index (NPI1 vs. 2, P=0.03) and tumour grade (grade 1 vs. 3, P=0.01) and was associated with better overall (P=0.037) and disease-free survival (P=0.048). The mRNA expression of Raptor was higher in tumours compared with normal tissues. Furthermore, the expression of Raptor was associated with a higher tumour grade (grade 1 vs. 3, P=0.027). A highly significant positive correlation between mTOR and hTERT (P<0.00001) was observed. These observations are consistent with the role of mTORC1 in the anti-apoptosis pathway and suggest that selective inhibitors of mTORC1 may be more efficacious in human breast cancer. Our findings support the hypothesis that mTORC1 is an important upregulator of telomerase in breast cancer.

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1	Shiota C, Woo JT, Lindner J, Shelton KD and Magnuson MA: Multiallelic disruption of the rictor gene in mice reveals that mTOR complex 2 is essential for fetal growth and viability. Dev Cell. 11:583–589. 2006. View Article : Google Scholar : PubMed/NCBI
2	Wu WK, Lee CW, Cho CH, Chan FK, Yu J and Sung JJ: RNA interference targeting raptor inhibits proliferation of gastric cancer cells. Exp Cell Res. 317:1353–1358. 2011. View Article : Google Scholar : PubMed/NCBI
3	Guertin DA and Sabatini DM: Defining the role of mTOR in cancer. Cancer Cell. 12:9–22. 2007. View Article : Google Scholar
4	Hudes G, Carducci M, Tomczak P, et al: Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 356:2271–2281. 2007. View Article : Google Scholar
5	Houghton PJ: Everolimus. Clin Cancer Res. 16:1368–1372. 2010. View Article : Google Scholar : PubMed/NCBI
6	Shor B, Zhang WG, Toral-Barza L, et al: A new pharmacologic action of CCI-779 involves FKBP12-independent inhibition of mTOR kinase activity and profound repression of global protein synthesis. Cancer Res. 68:2934–2943. 2008. View Article : Google Scholar : PubMed/NCBI
7	Noh WC, Mondesire WH, Peng J, et al: Determinants of rapamycin sensitivity in breast cancer cells. Clin Cancer Res. 10:1013–1023. 2004. View Article : Google Scholar : PubMed/NCBI
8	Jiang WG, Watkins G, Lane J, et al: Prognostic value of rho GTPases and rho guanine nucleotide dissociation inhibitors in human breast cancers. Clin Cancer Res. 9:6432–6440. 2003.PubMed/NCBI
9	Vezina C, Kudelski A and Sehgal SN: Rapamycin (AY-22,989), a new antifungal antibiotic. I Taxonomy of the producing streptomycete and isolation of the active principle. J Antibiot (Tokyo). 28:721–726. 1975. View Article : Google Scholar : PubMed/NCBI
10	Laplante M and Sabatini DM: mTOR signaling in growth control and disease. Cell. 149:274–293. 2012. View Article : Google Scholar : PubMed/NCBI
11	Bjornsti MA and Houghton PJ: The TOR pathway: a target for cancer therapy. Nat Rev Cancer. 4:335–348. 2004. View Article : Google Scholar : PubMed/NCBI
12	Brown EJ, Albers MW, Shin TB, et al: A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature. 369:756–758. 1994. View Article : Google Scholar : PubMed/NCBI
13	Gao X, Zhang Y, Arrazola P, et al: Tsc tumour suppressor proteins antagonize amino-acid-TOR signalling. Nat Cell Biol. 4:699–704. 2002. View Article : Google Scholar : PubMed/NCBI
14	Manning BD and Cantley LC: Rheb fills a GAP between TSC and TOR. Trends Biochem Sci. 28:573–576. 2003. View Article : Google Scholar : PubMed/NCBI
15	Yuen HF, Chan KK, Grills C, et al: Ran is a potential therapeutic target for cancer cells with molecular changes associated with activation of the PI3K/Akt/mTORC1 and Ras/MEK/ERK pathways. Clin Cancer Res. 18:380–391. 2012. View Article : Google Scholar : PubMed/NCBI
16	Inoki K, Ouyang H, Zhu T, et al: TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth. Cell. 126:955–968. 2006. View Article : Google Scholar : PubMed/NCBI
17	Zheng M, Wang YH, Wu XN, et al: Inactivation of Rheb by PRAK-mediated phosphorylation is essential for energy-depletion-induced suppression of mTORC1. Nat Cell Biol. 13:263–272. 2011. View Article : Google Scholar : PubMed/NCBI
18	Toschi A, Lee E, Thompson S, et al: Phospholipase D-mTOR requirement for the Warburg effect in human cancer cells. Cancer Lett. 299:72–79. 2010. View Article : Google Scholar : PubMed/NCBI
19	Guertin DA and Sabatini DM: The pharmacology of mTOR inhibition. Sci Signal. 2:pe242009.PubMed/NCBI
20	Shoji K, Oda K, Kashiyama T, et al: Genotype-dependent efficacy of a dual PI3K/mTOR inhibitor, NVP-BEZ235, and an mTOR inhibitor, RAD001, in endometrial carcinomas. PLoS One. 7:e374312012. View Article : Google Scholar : PubMed/NCBI
21	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. View Article : Google Scholar : PubMed/NCBI
22	McDonald PC, Oloumi A, Mills J, et al: Rictor and integrin-linked kinase interact and regulate Akt phosphorylation and cancer cell survival. Cancer Res. 68:1618–1624. 2008. View Article : Google Scholar : PubMed/NCBI
23	Mokbel K: The role of telomerase in breast cancer. Eur J Surg Oncol. 26:509–514. 2000. View Article : Google Scholar
24	Elkak A, Mokbel R, Wilson C, Jiang WG, Newbold RF and Mokbel K: hTERT mRNA expression is associated with a poor clinical outcome in human breast cancer. Anticancer Res. 26:4901–4904. 2006.PubMed/NCBI
25	Zhou C, Gehrig PA, Whang YE and Boggess JF: Rapamycin inhibits telomerase activity by decreasing the hTERT mRNA level in endometrial cancer cells. Mol Cancer Ther. 2:789–795. 2003.PubMed/NCBI
26	Bu X, Jia F, Wang W, Guo X, Wu M and Wei L: Coupled down-regulation of mTOR and telomerase activity during fluorouracil-induced apoptosis of hepatocarcinoma cells. BMC Cancer. 7:2082007. View Article : Google Scholar : PubMed/NCBI
27	Yamada O, Ozaki K, Akiyama M and Kawauchi K: JAK-STAT and JAK-PI3K-mTORC1 pathways regulate telomerase transcriptionally and posttranslationally in ATL cells. Mol Cancer Ther. 11:1112–1121. 2012. View Article : Google Scholar : PubMed/NCBI