Abstract 5048: The cholesterol metabolite, 27-hydroxycholesterol stimulates cell proliferation in prostate epithelial cell lines via estrogen receptor beta

Abstract

Abstract For every 6 men, 1 will be diagnosed with prostate cancer (PCa). Estrogen receptors are known to play a role in prostate carcinogenesis however, it is unclear whether the estrogenic effects are estrogen receptor α (ERα) or estrogen receptor β (ERβ) mediated. Although, it is speculated that ERα is associated with harmful effects on PCa while ERβ plays a more protective role on PCa, clinical trials using ERβ selective modulators have not shown improved clinical outcomes. Hence, the role of ERβ in PCa is yet to be understood. Recently a cholesterol oxidized metabolite (oxysterol), 27- hydroxycholesterol (27-OHC), was found to bind to both estrogen receptors (ERs) and act as a selective ER modulator (SERM). 27-OHC is the most prevalent cholesterol metabolite present in the blood with levels increasing with oxidative stress and age, especially in men. Increased 27-OHC levels are also found in individuals with hypercholesterolemia, which is also a risk factor for PCa. The role of 27-OHC through its action on estrogen receptors in the context of PCa is yet to be determined. We hypothesize that 27-OHC through ER activation has deleterious effect in PCa. We found that incubation with 27-OHC of RWPE-1, LNCaP and PC3 cells increased cell proliferation significantly. Using the ER inhibitor, Fulvestrant, we demonstrate that upon co-treatment with 27-OHC and fulvestrant, cell proliferation is reduced to basal levels, indicating the involvement of ERs. Interestingly, levels of ERβ, and to a lesser extent ERα, were increased following incubation of RWPE-1, LNCaP and PC3 with 27-OHC. Furthermore, in the presence of the ERβ specific inhibitor, PHTPP, we show that 27-OHC- induced proliferation is attenuated. Unexpectedly, while 27-OHC increases cell invasion in the moderately metastatic LNCaP, it decreases cell invasion in normal cells, RWPE-1 and highly metastatic, PC3. Altogether, our results propose dysregulated levels of 27-OHC as a new risk factor for prostate cancers with low metastatic potential. This indicates a novel role for 27-OHC in the etiopathogenesis of in PCa. Note: This abstract was not presented at the meeting. Citation Format: Shaneabbas Raza, Jared Schommer, Megan Meyer, Bin Guo, Kimberly Hammer, Othman Ghribi. The cholesterol metabolite, 27-hydroxycholesterol stimulates cell proliferation in prostate epithelial cell lines via estrogen receptor beta. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5048. doi:10.1158/1538-7445.AM2015-5048