Expression of 27-hydroxycholesterol metabolizing enzymes and breast cancer clinicopathological characteristics: The Multiethnic Cohort Study

Background: Obesity is a major modifiable risk factor for postmenopausal breast cancer prognosis. Mechanisms underlying the association between obesity and post-menopausal breast cancer include higher levels of estradiol, cholesterol, and inflammation. Circulating cholesterol is metabolized into 27-hydroxychlolesterol (27HC) by the sterol 27-hydroxylase enzyme (CYP27A1). 27HC is catabolized by the oxysterol 7alpha-hydroxylase enzyme (CYP7B1). 27HC can regulate breast cancer pathobiology by functioning as an endogenous selective estrogen receptor modulator in breast tumors. In this study, we examined the associations of expression levels of CYP27A1 and CYP7B1 in tumor tissue with clinicopathological characteristics of breast cancer in a multiethnic population. Methods: Invasive breast tumor tissue from 510 postmenopausal females (62 African American, 114 Japanese American, 93 Latino, 135 Native Hawaiian, and 106 White) in the Multiethnic Cohort Study were used for targeted profiling of gene expression using the NanoString nCounter Breast Cancer 360™ (BC360) Panel, including 51 additional custom genes. Generalized odds logistic regression analysis was conducted to examine associations of gene expression levels for CYP27A1 and CYP7B1 with clinicopathological characteristics -- stage, PAM50 molecular subtype (Luminal A, B, HER2-enriched, Basal-like) and NanoString Risk of Recurrence (ROR) score. Results: CYP27A1 expression was associated with a lower likelihood of advanced versus localized stage at diagnosis (OR=0.87; 95% CI 0.74, 1.02). No association was observed for CYP7B1 with stage. CYP27A1 expression was associated with a lower likelihood of HER2-enciched (OR=0.71; 95% CI 0.55, 0.92) and Luminal B (OR=0.71; 95% CI 0.58, 0.89) subtypes in comparison to Luminal A subtypes. CYP7B1 expression was associated with Basal-like (OR=1.23; 95% CI 1.02, 1.49), HER2-enriched (OR=0.59; 95% CI 0.43, 0.80), and Luminal B (OR=0.43; 95% CI 0.32, 0.58) subtypes in comparison to Luminal A. No significant association was observed for CYP27A1 and ROR categories (low, intermediate, and high). In contrast, CYP7B1 expression was associated with lower risk of recurrence score (ROR intermediate vs. low: OR=0.77; 95% CI 0.62, 0.96; ROR high vs. low: OR=0.56; 95% CI 0.40, 0.79). Conclusion: This study identified that gene expression levels of 27HC metabolizing enzymes, CYP27A1 and CYP7B1, in breast tumors were associated stage, breast cancer subtype, and risk of recurrence among a multiethnic population of women.