Abstract P1-04-09: mTORC1 and Rictor expression in human breast cancer: correlations with clinicopathological parameters and disease outcome

Abstract

Abstract BACKGROUND: 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). Raptor and Rictor are the core proteins for mTORC1 and mTORC2 respectively. There is a growing body of evidence that mTORC1 is up-regulated in many cancers and plays a role in carcinogenesis. The aim of the study was to investigate the mRNA expression of mTOR and Rictor in human breast cancer and examine the relationship between their expression and clinicopathological parameters. METHODS: Specimens of breast cancer (BC) tissues (N = 150) and normal tissues (N = 31) underwent RNA extraction and reverse transcription. mTOR and Rictor transcript levels were determined using real-time quantitative PCR. Expression levels were analyzed against tumor size, grade, nodal involvement, TNM stage, and clinical outcome over a 10 year follow-up period. RESULTS: Significantly higher mRNA transcript levels of mTOR were found in the breast cancer specimens compared to normal glandular tissue (p = 0.0018). The expression of mTOR mRNA was demonstrated to increase with increasing NPI (53 for NPI1 to 219 for NPI3) and tumor grade (37 for grade 2 vs. 159 for grade 3, p = 0.047). mTOR expression was found to be higher in ductal tumors compared with non-ductal tumors (p = 0.0014). The patients who developed recurrent disease or died from breast cancer had higher expression levels than those who had been disease-free after a median follow-up period of 10 years (p = 0.17). Higher expression levels were significantly associated with worse overall survival (p = 0.01). In contrast, higher levels of Rictor mRNA expression were found in normal breast tissue, lower NPI stage (NPI1 vs. 2: p = 0.03) and lower tumor grade (grade 1 vs. grade 3: p = 0.01). Patients with higher Rictor expression had a significantly better overall (p = 0.037) and disease-free (p = 0.048) survival. CONCLUSIONS: mTOR expression was found to be significantly higher in BC specimens compared to normal breast tissue. Higher transcript levels were significantly associated with unfavorable pathological parameters and adverse clinical outcomes. The core protein of the less predominant mTORC2 was associated with favorable pathological parameters and clinical outcome. Taken together 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 inhibitors in human breast cancer. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-04-09.