Abstract P6-04-11: LLGL2 is involved in resistance to tamoxifen in estrogen receptor-alpha positive breast cancer patients
Authors: Hisada Tomoka , Kondo Naoto , Endo Yumi , Asano Tomoko , Uemoto Yasuaki , Nishikawa Sayaka , Katagiri Yusuke , Terada Mitsuo , Kato Akiko , Dong Yu , Kato Hiroyuki , Takahashi Satoru , Toyama Tatsuya 
Published: March 2020

Background: Resistance to endocrine therapy and metastatic progression is a leading cause of death in estrogen receptor-alpha(ERα)-positive breast cancer patients. Recently, the scaffolding protein LLGL2 was reported to promote cellular proliferation in ERα-positive breast cancer cells. LLGL2 forms a trimetric complex with the leucine transport protein SLC7A5. LLGL2 and SLC7A5 were reported to be involved in resistance to tamoxifen treatment. Here, we investigated LLGL2 and SLC7A5 mRNA expression in breast cancer patients during long-term follow-up.

Materials and methods: A total of 627 invasive breast cancer tissues was available for analysis of LLGL2 mRNA using a TaqMan PCR system. We sought correlations between clinicopathological factors and levels of LLGL2 expression in these samples. We also examined the mRNA expression of SLC7A5. The median follow-up period was 10.8 years. Survival curves were analyzed using the Kaplan-Meier method. Cox proportional hazards regression analysis was used for univariate and multivariate analyses of prognostic values. Receiver operating characteristic (ROC) analysis was performed to determine the cut-off values of LLGL2 and SLC7A5 mRNA expression in breast cancers.

Results: We found a positive correlation between high expression of LLGL2 mRNA and shorter disease-free survival (DFS) in all patients analyzed (P=0.01). We also identified positive correlations between high expression of LLGL2 mRNA and shorter DFS and overall survival (OS) in ERα-positive breast cancer patients (P=0.0006 and P=0.004, respectively), and but not in ERα-negative patients (P=0.67 and P=0.63, respectively).

Positive correlations of LLGL2 mRNA expression with DFS and OS were observed in ERα-positive patients who received tamoxifen as an adjuvant therapy (P=0.02 and P=0.03, respectively). We also found positive correlations of SLC7A5 mRNA expression with DFS and OS in ERα-positive patients who received tamoxifen as an adjuvant therapy (P=0.006 and P=0.049, respectively); interestingly, this was not observed in ERα-positive patients who did not receive tamoxifen. Multivariate analysis indicated that high LLGL2 mRNA expression was an independent factor for prognosis both in breast cancer patients overall (Table 1) and ERα-positive breast cancer patients.

Conclusion: LLGL2 and SLC7A5 expression levels are associated with the prognosis of ERα-positive breast cancer patients, especially those who receive tamoxifen as an adjuvant therapy. Furthermore, higher expression of LLGL2 is an independent predictive factor of poor prognosis in ERα-positive breast cancer patients. LLGL2 and SLC7A5 could be promising candidate biomarkers and therapeutic targets in ERα-positive breast cancer patients who receive tamoxifen as an adjuvant therapy.

Table 1. Multivariate Cox regression analysis of factors associated with prognosis in all breast cancer patients.Variablesn (%)Multivariate (DFS)P valueHR (95% CI)Tumor size≤ 2cm241 (38)1&gt; 2cm383 (61)0.4771.14 (0.8-1.64)Node statusNegative340 (54)1Positive253 (40)&lt;0.00013.7 (2.61-5.25)Grade1164 (263)12 and 3445(71)0.0221.67 (1.07-2.69)ER statusPositive486 (77)1Negative131(21)0.0971.59 (0.92-2.75)LLGL2 mRNALow340 (54)1High287 (46)0.0231.46 (1.05-2.03)

Citation Format: Tomoka Hisada, Naoto Kondo, Yumi Endo, Tomoko Asano, Yasuaki Uemoto, Sayaka Nishikawa, Yusuke Katagiri, Mitsuo Terada, Akiko Kato, Yu Dong, Hiroyuki Kato, Satoru Takahashi, Tatsuya Toyama. LLGL2 is involved in resistance to tamoxifen in estrogen receptor-alpha positive breast cancer patients [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-04-11.