Aaminah Azhar

Introduction. Breast cancer (BC), the most frequently occurring cancer in women, has proven to be a major public health concern with approximately 1.7million cases diagnosed worldwide annually¹. The exact etiology of BC is unknown, however, there are a number of identified genetic and environmental risk factors that have been implicated in BC pathogenesis². Recently, a western diet with elevated dietary cholesterol has been associated with increasing the risk of breast cancer^3,4. Specifically 27-Hydroxycholesterol (27HC), a cholesterol metabolite, was identified. Studies that involve the ablation of CYP27A1, the rate limiting enzyme in 27-Hydroxycholesterol synthesis, show significantly reduction in metastasis in animal models^5,6,8. Since 90% of BC mortality is associated with metastasis, examining the pathways via which 27HC facilitates BC tumor metastasis provides insight on potential strategies for treatment of BC and modification of BC risk factors. One mechanism by which 27HC facilitates BC metastasis is through its actions on immune cells. Methods. A MMTV-PyMT mouse model that was pretreated with placebo or 27HC was utilized. Two mammary cancer models E0771 and Met1 were used⁶. a) The mice were treated with phosphate buffered saline (PBS) or clodronate liposome (CS) (a substance to eliminate myeloid cells) b) cell quantities, in primary and secondary tumors, of Polymorphonuclear neutrophil (PMN) and inflammatory monocytes (IM) were assessed by FACS analysis in E0771 cancer type c) mice were treated -Ly6G (a PMN depletor) d) -Ly6G treated tumors were quantified with fluorescence, e) in both E0771 and Met1 models levels of PMNs, -T Cells, and Cytotoxic CD8+ T cells were measured in primary tumors and distal lung sites by flow cytometry⁶. Results. In both Met1 and E0771 models, the 27HC pretreated mice treated with PBS vs. CS showed significantly more tumor fluorescence. The treatment of 27HC in mice resulted in increased recruitment of IMs and PMNs to the lungs. The colonizing effect of 27HC requires PMNs, as immune-depletion of PMNs with an antibody against -Ly6G ablates its metastatic effects. Treatment with 27HC increased the number of both PMNs and -T Cells with a corresponding decrease in cytotoxic CD8+ T cells⁶. Conclusions. The prometastic actions of 27-Hydroxycholesterol require both polymorphonuclear neutrophils and -T cells, and 27HC treatment decreases amounts of cytotoxic CD8+ T cells attenuating host immune response⁶. Although, Hmg-CoA reductase inhibition via statin therapy has proven to be beneficial in attenuating cancers⁷, it may be beneficial to specifically target 27HC by inhibiting CYP27A1 in the pathway.

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