Association of L-type amino acid transporter 1 (LAT1) with the immune system and prognosis in invasive breast cancer

Abstract

L-type amino acid transporter 1 (LAT1), also referred to as SLC7A5, is believed to regulate tumor metabolism and be associated with tumor proliferation. In invasive breast cancer, we clinicopathologically investigated the utility of LAT1 expression. LAT1 expression was evaluated via immunohistochemistry analyses in 250 breast cancer patients undergoing long-term follow-up. We assessed the relationships between LAT1 expression and patient outcomes and clinicopathological factors. Breast cancer-specific survival stratified by LAT1 expression was assessed. Human epidermal growth factor receptor 2 (HER2)-positive patients with metastasis received trastuzumab therapy. The density of tumor-infiltrating lymphocytes (TILs) was evaluated according to the International Working Group guidelines. In the current study, high LAT1 expression was significantly correlated with estrogen receptor (ER) negativity, progesterone receptor negativity, high histological grade, increased TILs, and programmed death ligand 1 positivity. Among the ER-positive and HER2-negative patients, high LAT1 was an independent indicator of poor outcomes (hazard ratio (HR) = 2.97; 95% confidence interval (CI), 1.16–7.62; p = 0.023). Moreover, high LAT1 expression was an independent poor prognostic factor in luminal B-like breast cancer with aggressive features (HR = 3.39; 95% CI 1.35–8.52; p = 0.0094). In conclusion, high LAT1 expression could be used to identify a subgroup of invasive breast cancer characterized by aggressive behavior and high tumor immunoreaction. Our findings suggest that LAT1 might be a candidate therapeutic target for breast cancer patients, particularly those with luminal B-like type breast cancer.

Novel iron chelator SK4 demonstrates cytotoxicity in a range of tumour derived cell lines

“…SK4 represents is the first iron chelator designed to gain cell entry through the LAT1 transporter exploiting "iron addiction" as well as dysregulated amino acid metabolism. LAT1 overexpression has been associated with poorer patient prognosis, and metastatic tumors, thus limiting iron chelation entry to the LAT1 transporter could be more suited to malignant tumors and could dampen potential side effects associated with iron chelation such as methemoglobinemia and myelosuppression (Yu et al, 2012a;Ichinoe et al, 2015;Ichinoe et al, 2021;Kurozumi et al, 2022). Interestingly, LAT1 is an antiport so while it can allow the entry of amino acids it has no effect on the total amount of amino acids within the cells but can influence the proportions of different amino acids, so SK4 may compete with amino acids for cell entry (Yanagida et al, 2001;Verrey et al, 2004).…”

“…We selected LAT1 as the mode of cell entry as LAT1 is commonly overexpressed in cancer including breast, prostate and ovarian (Sakata et al, 2009;Segawa et al, 2013;Kaira et al, 2015;Ichinoe et al, 2021;Kurozumi et al, 2022). Additionally, metastatic tumors tend to have higher levels of LAT1 (Ichinoe et al, 2015;Papin-Michault et al, 2016).…”

Amino acids and their roles in tumor immunotherapy of breast cancer

“…SLC7A5 mediates Leu uptake in breast cancer and enhances mTORC1 signaling, eventually resulting in aromatase inhibitor resistance 59,60 . Furthermore, SLC7A5 expression is positively associated with tumor size, histological grade, tumor infiltrating lymphocytes (TILs), and programmed death ligand 1 (PD‐L1) while negatively associated with ER and progesterone receptor (PR) in breast cancer 61 . A recent study showed that SLC7A5 was an immune infiltration‐related biomarker and breast cancer patients with high SLC7A5 expression were insensitive to paclitaxel and doxorubicin and had poor prognoses 62 …”

Characterization of substrates and inhibitors of the human heterodimeric transporter 4F2hc-LAT1 using purified protein and the scintillation proximity radioligand binding assay

“…The light subunit LAT1 (SLC7A5) ( Scalise et al, 2018 ) is expressed mainly in organs such as the brain, placenta, spleen and testis ( Nakamura et al, 1999 ; Prasad et al, 1999 ). Furthermore, LAT1 is overexpressed in numerous cancer types, e.g., brain ( Nawashiro et al, 2006 ), breast ( Kurozumi et al, 2022 ), gastric ( Ichinoe et al, 2011 ), lung ( Kaira et al, 2008 ), pancreatic ( Kaira et al, 2012 ), prostate ( Sakata et al, 2009 ), renal cell ( Betsunoh et al, 2013 ) and urologic cancer ( Nakanishi et al, 2007 ) (also see ( Wang and Holst, 2015 ) and ( Häfliger and Charles, 2019 ) for LAT1 expression in other tumors), and is used as a pathological factor for an unfavorable prognosis in patients. In such cancer cells, the nutritional uptake of neutral and essential neutral amino acids, and co-regulation of the mammalian target of rapamycin (mTOR) signaling pathway is mediated by the LAT1 transporter ( Nicklin et al, 2009 ).…”