A over AA as substrate, and makes 13-HODE in excess when both FA are available. This FA preference along 10760364 with the higher levels of LA compared to AA may be responsible for the preferential incremental accumulation of 13-HODE over 15-HETE in rapidly compared to more slowly proliferating cancers. Nonetheless, CO-1 and -2 also make 13-HODE and thereby appear to contribute to, for example, the ability of LA to stimulate the growth of MDA-MB-231 cell explants in mice by a CO inhibitor-dependent mechanism. In any event, 15-LO-2 oxygenates AA to 15-HETE but does not make 12-HETE and, like 12-LO and 5-LO, does not attack LA to make 13-HODE. Thus, the effect of CO-1, CO-2, and/or 15-LO-1 on breast cancer survival may reflect their production of 13-HODE. However, we found that: a) 13-HODE and 15-HETE levels were highly and significantly correlated in the cancer but not the normal breast tissue of all patients and patients with.20 Mib1 scores; b) patients with 15661576 #20 Mib1 scores showed none of these cancer tissue findings; and c) no significant correlations occurred between 13-HODE and the other metabolites. This result and the oxygenases’ metabolic profiles argue that the oxygenase capable of making 15-HETE and 13-HODE, 15-LO-1, is the major contributor to 13-HODE overproduction in rapidly proliferating breast cancer. This does not exclude a lesser but still significant role for CO-1/2 in adding to 13-HODE levels in this tissue. Indeed, the beneficial actions of CO inhibitors in breast cancer may reflect such a role. It should also be noted that although human breast cancer cells express all of the relevant oxygenases, the study of breast tissues as a whole does not inform on the cell type 481-53-8 cost originating FA metabolites. An influx of immune cells into a developing tumor may dramatically increase the availability of 13-HODE. The generation of 13-HODE by tissue macrophages is a major feature of late atherosclerotic lesions, a mechanism that may extrapolate to malignancies. Analysis of these tissues for the oxygenases by immunohistochemistry may also fail to identify the cells of origin since, as indicated in Introduction, the presence of an oxygenase does not necessarily indicate its metabolite production. PGE2 and D2 trended lower in the cancer tissue of patients with Mib1.20 scores, grade II & III disease, high mitosis rate, and node metastasis. While these trends failed to attain statistical significance, they did not occur with any other metabolite or marker. These results are compatible with a notion that reduced levels of PGE2 and D2 favor breast cancer proliferation. In conclusion, the metabolites and pathophysiology behind the contributions of FA oxygenases to poor survival in breast cancer has been ill-defined. We find that among the metabolites of the oxygenases known or found here to stimulate breast cancer cell proliferation, 13-HODE stands alone in associating 
with rapidly proliferating, rapidly dividing, aggressive grade, and perhaps metastasizing breast cancer. Three oxygenases make 13-HODE but correlation studies suggest that its major producer in rapidly proliferating breast cancer is 15-LO-1. Since 15-LO-1 makes other metabolites that are not characterized for proliferative activity in breast cancer cells or measured here, 13-HODE’s contribution to proliferation, division, and metastasis may be complemented or even superseded by other products of 15-LO-1. This caveat also applies to the trends of PGE2 and D2 to be negatively associated w