Impact of 27-Hydroxycholesterol, a Macrophage-Synthesized Estrogen Receptor Agonist, on Breast Cancer Pathophysiology

摘要

Our lab has recently demonstrated that 27-hydroxycholoesterol (27HC) acts as an estrogen. Macrophages have been shown to be a major source of 27HC, and macrophage infiltration is associated with more aggressive tumors. Therefore, the goal of this study is to determine the role of 27HC and macrophages in breast cancer pathology. In this reporting period we have initiated a breeding scheme to establish mice that carry the PyMT transgene with the following genotypes: CYP27A1+/+, CYP27A1-/-, CYP7B1+/+, CYP7B1-/-. We now have breeding mice from 3 out of 4 of these lines. Preliminary data from injection studies reveal that 27HC increases primary tumor growth, increases growth of total tumor burden and decreases the time to secondary tumor detection in PyMT mice. We have optimized conditions to differentiate macrophages. We have found that macrophages secrete factors that increase breast cancer cell proliferation, and provide evidence that one of these factors is likely to be 27HC. Furthermore, the proliferative factors secreted by macrophages appear to act on breast cancer cells in an ER dependant way. Finally, we have shown that a CYP27A1 inhibitor reduces the capacity of macrophages to promote breast cancer proliferation. In conclusion, our data thus far provides strong support for our hypothesis that macrophage secreted 27HC directly impacts the breast tumor environment.