Reduction of isoforms of 15-lipoxygenase (15-LOX)-1 and 15-LOX-2 in human breast cancer.
15-lipoxygenase (15-LOX) belongs to the structurally and functionally related nonheme iron dioxygenases family. It has two isoforms, type-1 (leukocyte type) and type-2 (epidermis type) and converts arachidonic acid to eicosanoids including the anti-cancer 13-HODE. In the current study, we investigate the expression of both isoforms of 15-LOX in human breast cancer (n=120) and normal mammary tissues (n=32), using immunohistochemistry and quantitative analysis of the gene transcripts. Both 15-LOX-1 and 15-LOX-2 were found in normal mammary epithelial cells and in vascular endothelial cells. The staining of both 15-LOX-1 and 15-LOX-2 was markedly weaker in breast cancer cells. Using quantitative analysis, it was found that the 15-LOX-1 and 15-LOX-2:CK19 ratios were lower in breast tumour tissues, compared with normal tissues (P=0.05 and P=0.035, respectively). Although no significant correlation was seen between either isoforms and nodal status and tumour grade, significantly lower ratio of 15-LOX-2:CK19 was seen in late stage breast tumours. Both 15-LOX-2 and 15-LOX-1 were found to be at significantly lower levels in tumours from patients who developed metastasis (P=0.0018 for 15-LOX-2 and P=0.031 for 15-LOX-1, compared with patients who remained disease free), and in patients who died of breast cancer related causes (P=0.043 and P=0.020 vs disease-free group, for 15-LOX-2 and 15-LOX-1, respectively). It was also demonstrated that ER-positive tumours had significantly lower levels of 15-LOX-2, but not 15-LOX-1, compared with ER-negative tumours (P=0.031). Finally, the study has shown that the 15LOX1:15LOX2 ratio had a strong value in predicting clinical outcome. Patients who developed metastasis, local recurrence and died of breast cancer had significantly lower ratio compared with those who remained disease free (P=0.0057, P=0.0075, P=0.0091, respectively). In conclusion, the current study reports aberrant expression of both isoforms of 15-LOX, 15-LOX-1 and 15-LOX-2, in human breast cancer. The reduction is correlated with the disease progression of breast cancer and a poor clinical outcome. The study has also reported a link between 15-LOX-2 and oestrogen receptor status in breast tumours. Both isoforms of 15-lipoxygenase have a tumour suppressing role in breast cancer.
Metastasis and Angiogenesis Research Group, University Department of Surgery, Wales of Medicine, Cardiff University, Cardiff CF14 4XN, UK. jiangw@cf.ac.uk
Wen G
WG
Jiang
Gareth
G
Watkins
Anthony
A
Douglas-Jones
Robert E
RE
Mansel
D001093:Arachidonate 15-Lipoxygenase / Q000276:immunology / Q000378:metabolism*; D001940:Breast / Q000166:cytology / Q000378:metabolism; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D011379:Prognosis; D020033:Protein Isoforms / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism
D020033:Protein Isoforms; D011960:Receptors, Estrogen; C458528:ALOX15B protein, human; D001093:Arachidonate 15-Lipoxygenase