Abstract
PurposeLysophosphatidic acid (LPA) is a bioactive molecule which participates in many physical and pathological processes. Although LPA receptor 6 (LPAR6), the last identified LPA receptor, has been reported to have diverse effects in multiple cancers, including breast cancer, its effects and functioning mechanisms are not fully known.MethodsMultiple public databases were used to investigate the mRNA expression of LPAR6, its prognostic value, and potential mechanisms in breast cancer. Western blotting was performed to validate the differential expression of LPAR6 in breast cancer tissues and their adjacent tissues. Furthermore, in vitro experiments were used to explore the effects of LPAR6 on breast cancer. Additionally, TargetScan and miRWalk were used to identify potential upstream regulating miRNAs and validated the relationship between miR-27a-3p and LPAR6 via real-time polymerase chain reaction and an in vitro rescue assay.ResultsLPAR6 was significantly downregulated in breast cancer at transcriptional and translational levels. Decreased LPAR6 expression in breast cancer is significantly correlated with poor overall survival, disease-free survival, and distal metastasis-free survival, particularly for hormone receptor-positive patients, regardless of lymph node metastatic status. In vitro gain and loss-of-function assays indicated that LPAR6 attenuated breast cancer cell proliferation. The analyses of TCGA and METABRIC datasets revealed that LPAR6 may regulate the cell cycle signal pathway. Furthermore, the expression of LPAR6 could be positively regulated by miR-27a-3p. The knockdown of miR-27a-3p increased cell proliferation, and ectopic expression of LPAR6 could partly rescue this phenotype.ConclusionLPAR6 acts as a tumor suppressor in breast cancer and is positively regulated by miR-27a-3p.
Highlights
Breast cancer accounts for 30% of the estimated incidence amongst all cancers in females and 15% of the estimated cancer-related deaths worldwide [1]
LPA receptor 6 (LPAR6) is downregulated in breast cancer, and decreased LPAR6 expression is correlated with poor clinicopathological features milk for 1.5 h at room temperature, the membrane was incubated with the corresponding primary antibodies followed by incubation with the appropriate horseradish peroxidaseconjugated secondary antibodies and imaging with electrochemiluminescence
◂Fig. 2 Decreased LPAR6 expression in breast cancer is significantly correlated with poor survival especially for hormone receptor-positive (HR +) patients. a–c Decreased LPAR6 expression significantly predicted poor overall survival (OS), disease-free survival (DFS), and distal metastasis-free survival (DMFS) in all patients. d–f Decreased LPAR6 expression significantly predicted poor OS, DFS, and DMFS in (HR +) patients. g–i Decreased LPAR6 expression could not predict OS and DMFS in HR- patients well but could predict DFS. j–o Decreased LPAR6 expression significantly predicted poor OS, DFS, and DMFS in patients with positive or negative lymph node metastasis assay was performed, and the results showed that LPAR6 protein level was lower in the para-tumor group than that in the tumor group (Fig. 1h)
Summary
Breast cancer accounts for 30% of the estimated incidence amongst all cancers in females and 15% of the estimated cancer-related deaths worldwide [1]. With improved early diagnosis and treatments, the total breast cancer-associated mortality in females has dropped by 31% [1]. Resistance to endocrine therapy and chemotherapy in patients. Endocrine Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, No.. This heterogeneity affects the effectiveness of treatments; novel targets for precision therapies must be identified
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