Molecular Aspects Of Prostate Cancer: LDL And Cholesterol Metabolism
Caroline BULL, University of Bristol, United Kingdom
MARTIN R. 1
,
HOLLY J. 2
,
PERKS C. 2
1 School of Social and Community Medicine, University of Bristol, United Kingdom
2 School of Clinical Sciences, University of Bristol, United Kingdom
Purpose: Epidemiological data suggest lifestyle factors are key in the development of aggressive prostate cancer (PCa). Low density lipoprotein (LDL) is a circulating blood lipid, modifiable through diet and drug intervention. A large body of literature supports an association between LDL and PCa, however, evidence is conflicting and causality has not been established.
Methods: Mendelian randomization techniques were used to investigate LDL as causal risk factor for PCa. Genetic risk scores representing a man’s relative exposure to LDL were generated for 22,249 PCa cases and 22,133 controls from 22 studies within the international PRACTICAL consortium. Logistic regression was used to estimate the causal effect of LDL on PCa. In a subsidiary analysis, we examined the effect of a variant in HMGCR on PCa outcomes. The relationship between circulating LDL and PCa was further investigated in human prostate cell lines PNT2, LNCaP, DU145 and PC3. Cell proliferation was measured by tritiated thymidine incorporation. Protein expression of key effectors in cholesterol metabolism was assessed using western immunoblotting.
Results: A genetically instrumented standard deviation change in LDL was not associated with all-cause PCa (OR 1.24, 95% CI; 0.90, 1.69, p=0.18), however, weak evidence suggested a role for LDL in high vs low grade PCa (OR 1.50, 95% CI; 0.92, 2.46, p=0.11). The rs12916-T variant in HMGCR (which has been used previously to mimic statin intervention) was associated with a weak protective effect on PCa (OR 0.97, 95% CI; 0.94, 1.00, p=0.03). The proliferative response to LDL-cholesterol differed between prostate cell lines and protein analysis by western immunoblotting indicated that cancerous cell lines express higher levels of key effectors in cholesterol metabolism.
Conclusions: This work presents evidence at the epidemiological and cellular level that perturbed LDL metabolism influences prostate cancer.