Correlation of L‐type amino acid transporter 1 and CD98 expression with triple negative breast cancer prognosis

Abstract

Triple negative breast cancer (TNBC) is a heterogeneous, aggressive cancer for which there is no effective chemotherapy or targeted therapy. We aimed to evaluate L-type amino acid transporter (LAT) 1 and CD98 expression immunohistochemically in patients with breast cancer, especially TNBC. Out of 129 patients, LAT1 was positive in 56 patients (43.4%), and CD98 was positive in 41 patients (31.8%). The positive ratio of LAT1 expression in luminal A cases was 7.9%, 30.0% in luminal B cases, 71.4% in HER2 cases and 64.0% in TN cases. HER2 and TN subtypes expressed LAT1 and CD98 at higher levels than luminal A and B subtypes (both P < 0.001). LAT1 and CD98 expression correlated with tumor size (LAT1, P = 0.010; CD98, P = 0.007), nuclear grade (LAT1, P < 0.001; CD98, P < 0.001) and Ki67 labeling index (LAT1, P < 0.001; CD98, P = 0.001). LAT1 and CD98 expression was negatively associated with ER and PgR (both P < 0.001). In TNBC, the 5-year disease-free rate of CD98+ (63.6%) or LAT1+/CD98+ (61.9%) patients was significantly worse than that of CD98) (89.3%) patients or those with no co-expression of LAT1 and CD98 (89.7%), respectively (P = 0.014, P = 0.009). The 5-year survival rates of CD98 positive/negative patients were 77.3% and 100% (P = 0.050), respectively, whereas that of patients with LAT1+/CD98+ (76.2%) was significantly worse (100%) (P = 0.040). Multivariate analysis confirmed that CD98+ or LAT1+/CD98+ expression were risk factors for relapse in TNBC (P = 0.023, P = 0.019). Thus, in the present study we show that LAT1 and CD98 expression are prognostic factors. Inhibition of these proteins might provide a new therapeutic strategy in TNBC. (Cancer Sci 2012; 103: 382-389) B reast cancer is a heterogeneous disease, and for many years invasive breast cancer was classified according to the extent of tumor spread, histological features and expression of the hormonal receptors, estrogen receptor (ER) and progesterone receptor (PgR). The subtypes that express hormonal receptors have been predicted to respond to endocrine therapy with tamoxifen (1) or aromatase inhibitors for two decades.(2) Recently, human epidermal growth factor receptor-2 (HER2) expression status has attracted a great deal of attention, because anti-HER2 therapies, such as trastuzumab treatment, have improved patient prognosis.(3-5) However, there are no targeted therapeutic agents for triple negative breast cancer (TNBC) (which is negative for ER, PgR and HER2) because of its heterogeneity, and the only treatment option is conventional systemic chemotherapy, despite its aggressive behavior.(6-12) Basal-like phenotype, which is classified by gene expression and low levels of ER, an absence of HER2 overexpression and positive basal-marker expression, clinically overlaps with TNBC.(12) Mutations in BRCA1 are reported to confer a high risk of development of the basal-like subtype, and loss of BRCA1 function is one of the determinants for the treatment of this phenotype. CD98 (4F2hc) was discovered through screening of mRNA to identify membrane pro...

L‑type amino acid transporter 1 expression is upregulated and associated with cellular proliferation in colorectal cancer

“…Previous reports (7,8,10) indicated that LAT1 expression was associated with depth of invasion, lymph node metastasis, and venous invasion in esophageal squamous cell carcinoma, and with lymph node metastasis in gastric carcinoma and non-small cell lung cancer. Moreover, high LAT1 expression was reported to be associated with poor prognosis in several types of cancer (7,8,(10)(11)(12)(13). In the present study, no relationship between high LAT1 expression and lymph node metastasis, which might influence the prognosis, was identified in CRC.…”

“…Increased LAT1 expression was frequently observed in the membrane and cytoplasm of cancer cells, while no LAT1 expression was detected in the normal mucosa. Regarding other types of cancer, the frequency of high LAT1 expression has been detected in 93 (59%) of 157 esophageal squamous cell carcinoma patients (7), 36 (41.4%) of 87 gastric cancer patients (8), 13 (24%) of 54 prostate cancer patients (9), 163 (51%) of 321 non small lung cancer patients (10), 89 (64%) of 139 biliary tract cancer patients (11), 51 (52.6%) in 97 pancreatic cancer patients (12), and 56 (43.4%) of 129 breast cancer patients (13). Thus, compared with other cancer types, the frequency of high LAT1 expression was relatively high in the cases of CRC examined in the present study.…”

“…The expression of LAT1 mRNA is restricted to certain organs, such as the brain, spleen, placenta, and testis (3)(4)(5). Furthermore, it has been reported that LAT1 is highly expressed in cancer tissue of various types of cancer, including oral squamous cell carcinoma (6), esophageal carcinoma (7), gastric cancer (8), prostate cancer (9), non-small cell lung carcinoma (10), biliary tract cancer (11), pancreatic cancer (12), and breast cancer (13).…”

L-type amino acid transporter 1 expression is highly correlated with Gleason score in prostate cancer

“…This discrepancy may occur as prostate cancers usually exhibit a slower growth compared to lung cancers. In other studies, lung adenocarcinomas and breast cancers showed much more intense and clearer immunoreactivity on the cell membranes (14,20) compared to the prostate adenocarcinomas discussed in this study. This discrepancy may also occur due to the relatively gentle character of prostate cancers.…”

“…Previous studies have shown that LAT1 is often excessively expressed in primary human neoplasms of various organs and is involved in tumor cell proliferation due to its function in transporting essential amino acids (4)(5)(6). Previous studies have demonstrated the upregulation of LAT1 immunohistochemically in prostate cancers (7), as well as in squamous cell carcinomas (8,9), gliomas (10), urothelial carcinomas (11), non-small cell lung cancers (12,13), breast cancers (14) and pancreatic cancers (15). In their previous study, Sakata et al (7) suggested that elevated LAT1 expression in prostate cancer core needle biopsy samples may be considered a novel biomarker for high-grade malignancy, but did not clarify the correlation between LAT1 expression and Gleason score, the most commonly used tool for grading the malignancy of prostate cancers.…”