Abstract 2133: Mechanisms by which 27-hydroxycholesterol promotes breast cancer metastasis
Authors: Liqian Ma, Amy E. Baek, Erik R. Nelson
Journal: Cancer Research (2018)

Abstract The purpose of this study is to investigate the mechanism by which the cholesterol metabolite, 27-hydroxycholesterol (27HC) promotes breast cancer metastasis. Breast cancer is the most commonly diagnosed cancer and among the leading causes of death in women in the United States. Elevated cholesterol is identified as a major risk factor of breast cancer onset and recurrence, while cholesterol-lowering drugs are associated with a good prognosis. Previous work has found that many of the effects of cholesterol on breast cancer progression are due to the actions of its primary metabolite, 27HC. 27HC is a ligand of both the estrogen receptor (ER) and liver X receptor (LXR). Intriguingly, the pro-metastatic effects of 27HC require the presence of myeloid-immune cells. This cell type has been implicated in suppressing acquired immunity, allowing cancer cells to escape immune-surveillance. Therefore, we hypothesize that 27HC suppresses the immune system to promote metastasis. To elucidate the immunomodulatory capacity of 27HC, we co-cultured vehicle- or 27HC-treated bone marrow-derived macrophages (BMDMs) with activated, CFSE-prelabeled T cells. As a readout of immune activation, we measured the resulting proliferation of T cells by flow cytometry. In support of our hypothesis, we found that 27HC-treated BMDMs inhibited T cell expansion in a dose dependent manner. In order to determine the mechanisms by which 27HC-treated BMDMs suppress T cell proliferation, we first evaluated the relative contributions of two receptors known to bind 27HC: the ERs and LXRs. To this end, BMDMs were treated with various combinations of pharmacologic agonists or antagonists of the ERs or LXRs. These treated BMDMs were subsequently co-cultured with activated T cells to study their impact on T cell proliferation. Interestingly, a combination treatment of suboptimal doses of an ER antagonist and LXR agonist moderately reduced T cell expansion, similar to 27HC. Therefore, our results suggest that 27HC affects the microenvironment of breast cancer by altering the activity of antigen-presenting cells through the modulation of the ER and LXR. This in turn reduces the expansion of T cell function, ultimately resulting in tumor progression. Our ongoing work is aimed at further elucidating the crosstalk between the ERs and LXRs and identifying the downstream targets of 27HC involved in mediating this immune-suppressive phenotype. Our work is of considerable importance given the prevalence of metastatic breast cancer and that the cholesterol axis is highly amenable to therapeutic targeting. This work was supported by the National Cancer Institute of the National Institutes of Health (R00CA172357, E.R.N.). Citation Format: Liqian Ma, Amy E. Baek, Erik R. Nelson. Mechanisms by which 27-hydroxycholesterol promotes breast cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2133.