Grant: Master's Award: Canada Graduate Scholarships

Breast Cancer; Estrogen Receptor; Growth Factors; N-Myristoyltransferase; Patient Stratification; Predictive Biomarker; Protein Modification; Side Directed Mutagenesis; Signal Transduction; Transcription Factor

Proposed research aims at understanding the mechanism of breast cancer progression and identifying biomarkers that will predict better clinical outcome and may potentially be therapeutic targets for the treatment of breast cancer. Recent clinical trails- BOLERO and HORIZON were designed to determine the efficacy of mechanistic target of rapamycin (mTOR) inhibitors in augmenting recurrence free survival. The results of both the trials contradict each other. BOLERO trial showed increase in recurrence free survival whereas, HORIZON showed no benefit. The lack of efficacy in HORIZON trial could be due to the mTOR inhibitor used and varying degrees of individual metabolism of the drugs used based on pharmacogenomic heterogeneity. This suggests that there is a need for more accurate biomarkers, other than estrogen receptor (ERα), to select patients for whom mTOR inhibitor combined with endocrine treatments will be effective. Our research group has revealed hitherto unknown relationship between N-myristoyltransferase 1 (NMT1) and mTOR. Furthermore, we demonstrated that NMT1 is a downstream target of insulin or insulin like growth factor (IGF)/mTOR pathway. Recently, we found that localization of NMT1 in the nuclei of ERα positive breast cancer cells predicts better clinical outcome when patients undergo endocrine therapy. Therefore, I propose to study the relationship between mTOR pathway and NMT1 in the pathogenesis of breast cancer. The results of my proposed research may lead to the identification of biomarkers that will allow clinicians to stratify patients for endocrine therapy or combination therapy of aromatase and mTOR inhibitors.