The significance of cholesterol and its metabolite, 27-hydroxycholesterol in breast cancer

Abstract

Although significant advances in the treatment of breast cancer have been made, in particular in the use of endocrine therapy, de novo and aquired resistance to therapy, and metastatic recurrence continue to be major clinical problems. Given the high prevalence of breast cancer, new life-style or chemotherapeutic approaches are required. In this regard, cholesterol has emerged as a risk factor for the onset of breast cancer, and elevated cholesterol is associated with a poor prognosis. While treatment with cholesterol lowering medication is not associated with breast cancer risk, it does appear to be protective against recurrence. Importantly, the cholesterol axis represents a potential target for both life-style and pharmacological intervention. This review will outline the clinical and preclinical data supporting a role for cholesterol in breast cancer pathophysiology. Specific focus is given to 27-hydroxycholesterol (27-OHC; (3β,25R)-Cholest-5-ene-3,26-diol)), a primary metabolite of cholesterol that has recently been defined as an endogenous Selective Estrogen Receptor Modulator. Future perspectives and directions are discussed.

Keywords: 27-Hydroxychoelsterol; Breast cancer; Cholesterol; Estrogen receptor; Liver x receptor; Selective estrogen receptor modulator.

Figure 1

Tumoral expression of enzymes involved in the metabolism of 27-hydroxychoelsterol (27-OHC) are prognostic of time to recurrence. (a) Elevated mRNA expression of CYP7B1 mRNA, the enzyme responsible for the catabolism of 27-OHC, is associated with an increased recurrence free survival time. (b) Elevated mRNA expression of CYP27A1, the enzyme responsible for conversion of cholesterol to 27-OHC is associated with increased recurrence free survival time. Analysis was performed by the online Kaplan Meier Plotter tool (Gyorffy, Lanczky, Eklund et al., 2010). Patients were parsed into tertiles based on mRNA expression, as indicated on the plots.