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.
Subject(s)
Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Carrier Proteins/biosynthesis , Multiprotein Complexes/biosynthesis , TOR Serine-Threonine Kinases/biosynthesis , Adaptor Proteins, Signal Transducing/agonists , Adaptor Proteins, Signal Transducing/biosynthesis , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolism , Apoptosis/genetics , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Carrier Proteins/genetics , Carrier Proteins/metabolism , Disease-Free Survival , Female , Humans , Mechanistic Target of Rapamycin Complex 1 , Multiprotein Complexes/antagonists & inhibitors , Multiprotein Complexes/genetics , Multiprotein Complexes/metabolism , Prognosis , RNA, Messenger/genetics , Rapamycin-Insensitive Companion of mTOR Protein , Regulatory-Associated Protein of mTOR , Signal Transduction/genetics , TOR Serine-Threonine Kinases/antagonists & inhibitors , TOR Serine-Threonine Kinases/genetics , TOR Serine-Threonine Kinases/metabolism , Telomerase/genetics , Telomerase/metabolismABSTRACT
UNLABELLED: This pilot study is the first to focus on the potential role of death-associated protein 1 (DAP1) in human breast cancer. MATERIALS AND METHODS: A total of 153 samples were studied. DAP1 transcription levels were determined using quantitative polymerase chain reaction (qPCR). Transcript levels within breast cancer specimens were compared to those of normal background tissues and correlated with clinicopathological data accumulated over a 10-year follow-up period. RESULTS: The expression of DAP1 mRNA was demonstrated to decrease with increasing Nottingham Prognostic Index (NPI2 vs. NPI3, p=0.0026), and TNM stage (TNM1 vs. 4, p=0.0039). Lower DAP1 expression levels were significantly associated with local recurrence (p=0.02) and distant metastasis (p=0.001). CONCLUSION: This study demonstrates an inverse association between DAP1 mRNA levels and tumour stage and clinical outcome in breast cancer; thus, providing evidence that DAP1 plays a pro-apoptotic role in human breast cancer. The relationship between oncogenesis and the autophagy pathway merits further investigation.
Subject(s)
Apoptosis Regulatory Proteins , Breast Neoplasms , RNA, Messenger/metabolism , Apoptosis/genetics , Apoptosis Regulatory Proteins/genetics , Apoptosis Regulatory Proteins/metabolism , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Female , Gene Expression Regulation, Neoplastic , Humans , Neoplasm Staging , RNA, Messenger/genetics , Treatment OutcomeABSTRACT
BACKGROUND: This pilot study is the first to focus on the potential role for death-associated protein 3 (DAP3) in human breast cancer. MATERIALS AND METHODS: A total of 153 samples were studied. The levels of transcription of DAP3 were determined using quantitative polymerase chain reaction (qPCR). Transcript levels within breast cancer specimens were compared to those of normal background tissues and correlated with clinicopathological data accumulated by over a 10-year follow-up period. RESULTS: The expression of DAP3 mRNA was demonstrated to decrease with increasing Nottingham Prognostic Index (NPI2 vs. 3, p=0.036), TNM stage (TNM1 vs. 3, p=0.07), and tumour grade (grade 1 vs. 3, p=0.08). Lower DAP3 expression levels were significantly associated with local recurrence (p=0.013), distant metastasis (p=0.0057) and mortality (p=0.019). CONCLUSION: This study demonstrates an inverse association between DAP3 mRNA levels and tumour stage and clinical outcome in breast cancer, consistent with the pro-apoptosis function of DAP3. Further research is required in order to confirm our findings and clarify the mechanisms that regulate DAP3 expression in human breast cancer.
