Abstract
18F-FDG PET/CT has been used as an indicator of chemotherapy effects, but cancer cells can remain even when no FDG uptake is detected, indicating the importance of exploring other metabolomic pathways. Therefore, we explored the amino acid metabolism, including L-type amino acid transporter-1 (LAT1), in breast cancer tissues and clarified the role of LAT1 in therapeutic resistance and clinical outcomes of patients. We evaluated LAT1 expression before and after neoadjuvant chemotherapy and examined the correlation of glucose uptake using FDG-PET with the pathological response of patients. It revealed that LAT1 levels correlated with proliferation after chemotherapy, and amino acid and glucose metabolism were closely correlated. In addition, LAT1 was considered to be involved in treatment resistance and sensitivity only in luminal type breast cancer. Results of in vitro analyses revealed that LAT1 promoted amino acid uptake, which contributed to energy production by supplying amino acids to the TCA cycle. However, in MCF-7 cells treated with chemotherapeutic agents, oncometabolites and branched-chain amino acids also played a pivotal role in energy production and drug resistance, despite decreased glucose metabolism. In conclusion, LAT1 was involved in drug resistance and could be a novel therapeutic target against chemotherapy resistance in luminal type breast cancer.
Highlights
18F-FDG PET/CT has been used as an indicator of chemotherapy effects, but cancer cells can remain even when no FDG uptake is detected, indicating the importance of exploring other metabolomic pathways
In patients with estrogen receptor (ER)-negative/human epidermal growth factor receptor-2 (HER2)-negative tumors, the Pre-L-type amino acid transporter-1 (LAT1)-positive group had a significantly higher pathological complete response (pCR) rate than the Pre-LAT1-negative group (45.83% vs 33.33%, p = 0.0016). These findings indicated that the Pre-LAT1 status was significantly correlated with response to chemotherapy in both ER-positive and HER2-negative breast cancer patients
As the clinical study indicated that LAT1 was involved in drug resistance in ER-positive tumors, we used MCF7 cells to examine the biological function of LAT1 following drug treatment
Summary
18F-FDG PET/CT has been used as an indicator of chemotherapy effects, but cancer cells can remain even when no FDG uptake is detected, indicating the importance of exploring other metabolomic pathways. We explored the amino acid metabolism, including L-type amino acid transporter-1 (LAT1), in breast cancer tissues and clarified the role of LAT1 in therapeutic resistance and clinical outcomes of patients. We evaluated LAT1 expression before and after neoadjuvant chemotherapy and examined the correlation of glucose uptake using FDG-PET with the pathological response of patients. It revealed that LAT1 levels correlated with proliferation after chemotherapy, and amino acid and glucose metabolism were closely correlated. Breast carcinoma cells persist in more than half of patients who display no FDG uptake or in those who achieve complete metabolic response (CMR)[15], indicating that breast cancer cells utilize metabolomic pathways besides that of glucose
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