Triple-negative breast cancer (TNBC) is considered to be a notorious type of cancer due to its aggressive metastatic potential and poor prognosis. Recent evidence suggests that BLT2, a low-affinity LTB4 receptor is critically associated with the phenotypes of TNBC cells, including invasion, metastasis, and survival. Furthermore, in a group of 545 breast cancer patients with metastasis, we observed that the high-BLT2 subgroup had a lower disease-free-survival rate than the low-BLT2 subgroup. Thus, we theorized that anti-BLT2 strategies could facilitate the development of new therapies used for TNBC. This review focuses on recent discoveries regarding BLT2 and its roles in as a novel prognostic biomarker in TNBC.

Inflammation and inflammatory mediators are intimately linked with chemoresistance through complex pathways in the tumor microenvironment. However, the mechanism by which inflammatory mediators (e.g., eicosanoids) contribute to chemoresistance remains elusive. In this study, we found that the low-affinity leukotriene B4 receptor-2 (BLT2) and its ligand leukotriene B4 were highly up-regulated in cisplatin-resistant SK-OV-3 ovarian cancer cells and play critical roles in mediating the chemoresistance through the activation of signal transducer and activator of transcription-3 (STAT-3) and the subsequent up-regulation of interleukin-6 (IL-6). BLT2 depletion with siRNA clearly abolished the chemoresistance to cisplatin in SK-OV-3 ovarian cancer cells and further increased cell sensitivity to cisplatin chemotherapy by down-regulating the 'STAT-3-IL-6' cascade. Enlarged tumor formation due to the cisplatin resistance of SK-OV-3 cells in cisplatin-treated athymic mice was also substantially reduced by co-treatment with the BLT2 inhibitor in vivo. Our study demonstrates that BLT2 is a novel contributor to cisplatin resistance in SK-OV-3 ovarian cancer cells and thus may be a potential therapeutic target for the treatment of cisplatin-resistant ovarian cancer.

Although lung cancer is the leading cause of cancer-related deaths worldwide and KRAS is the most frequently mutated oncogene in lung cancer cases, the mechanism by which KRAS mutation drives lung cancer has not been fully elucidated. Here, we report that the expression levels of leukotriene B4 receptor-2 (BLT2) and its ligand-producing enzymes (5-LOX, 12-LOX) were highly increased by mutant KRAS and that BLT2 or 5-/12-LOX blockade attenuated KRAS-driven lung cell proliferation and production of interleukin-6 (IL-6), a principal proinflammatory mediator of lung cancer development. Next, we explored the roles of BLT2 and 5-/12-LOX in transgenic mice with lung-specific expression of mutant KRAS (KrasG12D) and observed that BLT2 or 5-/12-LOX inhibition decreased IL-6 production and tumor formation. To further determine whether BLT2 is involved in KRAS-driven lung tumor formation, we established a KrasG12D/BLT2-KO double-mutant mouse model. In the double-mutant mice, we observed significantly suppressed IL-6 production and lung tumor formation. Additionally, we observed high BLT2 expression in tissue samples from patients with KrasG12D-expressing lung adenocarcinoma, supporting the contributory role of BLT2 in KRAS-driven human lung cancer. Collectively, our results suggest that BLT2 is a potential contributor to KRAS-driven lung cancer and identify an attractive therapeutic target for KRAS-driven lung cancer.

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