Gene Signatures and Potential Therapeutic Targets of Amino Acid Metabolism in Estrogen Receptor-Positive Breast Cancer(1/2)

Estrogen receptor-positive (ER+) breast cancer patients often have a good prognosis; however, more than 30% of patients receiving adjuvant tamoxifen finally recurrence and die from distance metastasis due to drug resistance. To solve this clinical issue, several inhibitors of the Mammalian Target Of Rapamycin (mTOR)/Phosphoinositide 3-kinase (PI3K)/ Protein kinase B (PKB) pathway have been combined with tamoxifen in clinical trials of ER+ tumors. Recent research demonstrated that tamoxifen resistance had one of the best interaction with amino acid transporters and mTOR signaling. Besides, Interferon Alpha Inducible Protein 6 (G1P3) was reported to induces tamoxifen resistance and inhibits detachment-induced cell death (anoikis). Although research has been conducted regarding anoikis resistance and cell death pathways in cancer cells, the relationship between anoikis resistance, amino acid metabolism, and tamoxifen resistance requires further study. In this research proposal, we will identify the rate-limiting enzyme involved in amino acid metabolism that is associated with ER+ breast cancer by integrating numerous bioinformatics tools and laboratory studies. Two Specific Aims are proposed in this research project: Aim1: To explore the effect of amino acid metabolism-related genes on ER+ and tamoxifen resistance breast cancer. Aim2: To investigate whether amino acid metabolism-related genes will participate in tamoxifen resistance and anoikis via mTOR or other signal pathways. In addition, we will use small-molecule inhibitors to evaluate the therapeutic effects of ER+ breast cancer models. Research Approach: Aim 1: We will use data mining to identify amino acid metabolic-related genes of ER+ breast cancer, and use MCF-7 and T47D cell line, orthotopic model, as well as the next-generation sequencing to explore the crosstalk between tamoxifen resistance and amino acid metabolism in ER+ breast cancer development. Aim 2: We will use FDA-approved drug from Connectivity Map and small-molecule or inhibitor of amino acid transporter to evaluate the therapeutic effects of ER+ and tamoxifen resistance breast cancer. Significance: Amino acid metabolism genes play crucial roles in tumor progression, and the present study will establish a critical basis for developing prospective drug targets and biomarkers for ER+ and tamoxifen resistance breast cancer.