Leukotriene B4 receptors abnormal gene expression is associated with either shorter or longer survival in breast cancer patients depending on the intrinsic tumour molecular subtype

Abstract

Abstract Background Leukotrienes receptor signaling is involved in tumor development and progression. Expression of leukotriene B4 receptors 1 and 2 (LTB4R and LTB4R2) promotes cell proliferation, survival, migration and metastasis. Aberrant LTB4R gene expression blocks anti-proliferative responses of TGF-β1 in breast cancer (BC) cell lines. LTB4R2 ectopic expression is associated with increased invasiveness of BC cells. Earlier, we reported LTB4R and LTB4R2 genes abnormal demethylation that is potent of initiating ectopic gene expression in a subset of triple-negative BC (TNBC) samples. Methods We acquired the TCGA BRCA level 3 RNA-seq data and clinical datasheet using TCGA data portal. LTB4R/LTB4R2 gene expression cut-off values were defined using maximally selected rank statistics. Kaplan-Meier overall survival (OS) curves were compared with Mantel-Cox (log-rank) method. Results TNBC exhibit a significantly lower survival probability in LTB4R expressing group. Vice versa, in Normal-Like and LumB subtypes absence of LTB4R and LTB4R2 expression respectively is associated with shorter OS (Table). Table: 57P . Overall survival comparison in various molecular BC subtypes. Asteriks (*) stand for p-value less then 0.05. Median OS are presented in days Expression groups/ Molecular groups No subtyping LumA LumB HER2 TNBC Normal-Like Median OS p-value Median OS p-value Median OS p-value Median OS p-value Median OS p-value Median OS p-value LTB4R = high 3945 0.42 3926 0.81 3941 0.059 6456 0.08 7455 0.0029* 4267 0.0034* LTB4R = low 3736 3873 2483 2127 NA 1688 LTB4R2 = high 3945 0.53 3873 0.51 3941 0.026* 6456 0.59 7455 0.74 4267 0.58 LTB4R2 = low 3472 2965 2573 3063 3472 1759 Conclusions Our findings suggest that LTB4R/LTB4R2 gene expression is a new potential BC prognostic biomarker, yet its use requires proper molecular subtyping of the tumors, as far as prognosis would depend upon the intrinsic tumor subtype. This also applies to the potential use of LTB4R/LTB4R2 expression as a marker predictive of tumors sensitivity to leukotriene receptor inhibitors, in case they enter clinical studies. Legal entity responsible for the study Research Centre for Medical Genetics. Funding The research was carried out within the state assignment of Ministry of Science and Higher Education of the Russian Federation. Disclosure All authors have declared no conflicts of interest.