Targeting Amino Acid Metabolic Reprogramming via L-Type Amino Acid Transporter 1 (LAT1) for Endocrine-Resistant Breast Cancer

Simple Summary L-type amino acid transporters such as LAT1 and LAT3 are associated with the uptake of essential amino acids. In particular, LAT1 regulates mammalian target of rapamycin complex 1 (mTORC1) signaling and cell proliferation by regulating leucine uptake. The purpose of this study is to clarify amino acid metabolism via LAT1 and LAT3 in breast cancer and the potential roles of LAT1 in the development of therapeutic resistance and clinical outcome of the patients. Results demonstrated that high LAT1 status was associated with tumor progression in breast cancer patients who received neoadjuvant hormone therapy (NAH), and LAT1 expression in the estrogen deprivation-resistant (EDR) breast carcinoma cell lines were upregulated. JPH203, a selective LAT1 inhibitor, demonstrated inhibitory effects on cell proliferation in the EDR cells. Therefore, LAT1 could serve not only as a prognosis biomarker but also a therapeutic target in estrogen receptor (ER)-positive breast cancer patients. The PI3K/Akt/mTOR pathway has been well known to interact with the estrogen receptor (ER)-pathway and to be also frequently upregulated in aromatase inhibitor (AI)-resistant breast cancer patients. Intracellular levels of free amino acids, especially leucine, regulate the mammalian target of rapamycin complex 1 (mTORC1) activation. L-type amino acid transporters such as LAT1 and LAT3 are associated with the uptake of essential amino acids. LAT1 expression could mediate leucine uptake, mTORC1 signaling, and cell proliferation. Therefore, in this study, we explored amino acid metabolism, including LAT1, in breast cancer and clarified the potential roles of LAT1 in the development of therapeutic resistance and the eventual clinical outcome of the patients. We evaluated LAT1 and LAT3 expression before and after neoadjuvant hormone therapy (NAH) and examined LAT1 function and expression in estrogen deprivation-resistant (EDR) breast carcinoma cell lines. Tumors tended to be in advanced stages in the cases whose LAT1 expression was high. LAT1 expression in the EDR cell lines was upregulated. JPH203, a selective LAT1 inhibitor, demonstrated inhibitory effects on cell proliferation in EDR cells. Hormone therapy changed the tumor microenvironment and resulted in metabolic reprogramming through inducing LAT1 expression. LAT1 expression then mediated leucine uptake, enhanced mTORC1 signaling, and eventually resulted in AI resistance. Therefore, LAT1 could be the potential therapeutic target in AI-resistant breast cancer patients.