title: Aberrant expression of 5-lipoxygenase-activating protein (5-LOXAP) has prognostic and survival significance in patients with breast cancer.
abstract: 5-lipoxygenase (5-LOX)-activating protein, 5-LOXAP also known as LOX5AP or FLAP, is a protein that works closely with 5-LOX in regulating the metabolism of arachidonate. Some of the eicosanoid products of 5-LOX/5-LOXAP are known to play active roles in the function of cancer cells, including breast cancer cells. The current study investigated the expression of 5-LOXAP in clinical breast cancer and the prognostic impact of 5-LOXAP and 5-LOX in patients with breast cancer. A cohort of breast tumour tissues (n = 122) with normal background tissues (n = 32) were investigated. 5-LOXAP and 5-LOX transcripts were determined using RT-PCR and quantitative RT-PCR. Levels of the transcripts were analysed against clinical and pathological information. Breast tumour tissues had significantly higher levels of 5-LOX transcript compared with normal tissues (P = 0.015). The transcript was seen at significantly higher levels in node positive tumours than that in node negative tumours (P = 0.02). The prognostic significance was assessed using both a prognostic index and clinical outcome. Value of 5-LOXAP was first demonstrated when using the Nottingham Prognostic Index (NPI) as an indicator, in that patients with predicted poor prognosis had significantly higher levels of 5-LOXAP than patients with good prognosis (P = 0.0407). Furthermore, patients who died of breast cancer-related causes had significant higher levels of 5-LOXAP than those patients who remained disease free, following a median 10-year followup. A survival analysis has shown that high levels of 5-LOXAP were significantly correlated with overall survival (mean survival 109.6 month vs. 139.4 months, in tumour from patients with high and low levels of 5-LOXAP, P = 0.05). The same disadvantage of high levels of 5-LOXAP was also seen with disease-free survival (105.2 months vs. 135.6 months, P = 0.017). Analysis of 5-LOXAP together with 5-LOX transcript did not enhance the significance of the survival. However, when 5-LOXAP was considered together with 12-LOX, it improved the predictive power for both overall and disease-free survival (109.0 month vs. 143.1 months, P = 0.0156 for overall survival and 98.3 months vs. 141.3 months for disease-free survival, P = 0.0022). In conclusion, 5-LOXAP expression was aberrant in human breast cancer, particularly in aggressive tumours. Furthermore, 5-LOXAP had a significant prognostic value in patients with breast cancer. This identifies 5-LOXAP as a potential therapeutic target in breast cancer.
authors.affiliation: Metastasis and Angiogenesis Research Group, University Department of Surgery, School of Medicine Cardiff University, Heath Park, Cardiff, CF1A 4XN, UK. jiangw@cf.ac.uk
authors.forename: Wen G
authors.initials: WG
authors.lastname: Jiang
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Douglas-Jones
authors.forename: Robert E
authors.initials: RE
authors.lastname: Mansel
mesh_terms: D058927:5-Lipoxygenase-Activating Proteins; D001943:Breast Neoplasms / Q000378:metabolism* / Q000401:mortality* / Q000556:secondary; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D015331:Cohort Studies; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008207:Lymphatic Metastasis; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D011237:Predictive Value of Tests; D011379:Prognosis; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis
chemical_list: D058927:5-Lipoxygenase-Activating Proteins; C548592:ALOX5AP protein, human; D002352:Carrier Proteins; D008565:Membrane Proteins; D012333:RNA, Messenger