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

Sasagu Kurozumi,Tetsunari Oyama,Takehiko Yokobori,Nigel P Mongan,Chikako Sekine,Hiroshi Matsumoto,Ayaka Katayama,Kyoichi Kaira,Takaya Makiguchi,Mio Furuya,Yoshikatsu Kanai,Masafumi Kurosumi,Sho Shiino,Takaaki Fujii,Emad A Rakha,Ken Shirabe,Chikako Honda,Jun Horiguchi

doi:10.1038/s41598-022-06615-8

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.

Highlights

L-type amino acid transporter 1 (LAT1), referred to as SLC7A5, is believed to regulate tumor metabolism and be associated with tumor proliferation
High LAT1 expression was significantly correlated with estrogen receptor (ER) negativity (p < 0.0001), progesterone receptor (PgR) negativity (p < 0.0001), human epidermal growth factor receptor 2 (HER2) positivity (p < 0.0001), large tumor size (p = 0.016), and high histological grade (p < 0.0001) (Table 1)
Survival curves stratified by LAT1/tumor-infiltrating lymphocytes (TILs) and LAT1/programmed death ligand 1 (PD-L1) levels are shown in Supplementary Fig. 1

Summary

Introduction

L-type amino acid transporter 1 (LAT1), referred to as SLC7A5, is believed to regulate tumor metabolism and be associated with tumor proliferation. 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). High LAT1 expression is closely related to the proliferation of tumor cells and angiogenesis in various types of cancer, such as melanoma[16], lung cancer[17], pancreatic cancer[18], gastrointestinal cancer[19,20], and triple-negative BCa (TNBC)[21]. A previous large BCa study by El Ansari et al.[23] reported that a high LAT1 expression level was associated with high proliferation potential, as indicated by the high Nottingham prognostic index and Ki67 labeling index; high LAT1 expression level was a poor prognostic factor in luminal B-like type breast tumors. We confirmed the correlation between LAT1 protein expression and key clinicopathological factors, including TILs and PD-L1, in BCa patients

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Conclusion