Abstract C073: The association between 27-hydroxycholesterol metabolizing enzymes, CYP27A1 and CYP7B1, expression and mortality in a multiethnic U.S. population of breast cancer patients

Breast cancer is the most common cancer and the second leading cause of cancer death among women in the U.S. Obesity is one of the most significant risk factors for breast cancer in postmenopausal women and is a key predictor for poor prognosis. Postulated mechanisms underlying the association between obesity and post-menopausal breast cancer include higher levels of estradiol, hypercholesterolemia, and inflammation. 27-hydroxychlolesterol (27HC) is produced when cholesterol is metabolized by the enzyme, sterol 27-hydroxylase (CYP27A1), a conversion that is reversed by the catabolizing enzyme, oxysterol 7α-hydroxylase (CYP7B1). Laboratory studies established that 27HC is an endogenous selective estrogen receptor modulator (SERM) capable of promoting breast cancer growth by binding to the estrogen receptor (ER) and by increasing the metastatic potential of breast tumors through the activation of the liver X receptor (LXR). However, there are significant gaps in the understanding of 27HC’s complex role in breast cancer pathobiology and breast cancer survival, particularly in multiethnic populations. We examined the association between protein expression profiles for CYP27A1 and CYP7B1 with breast cancer-specific and overall mortality in a multiethnic U.S. population by conducting immunohistochemical analyses, utilizing commercially available antibodies to CYP27A1 and CYP7B1, on a total of 787 invasive breast tumors included in a population-based tissue microarray. Based on Cox proportional hazards regression analysis with adjustment for age, stage, ER and progesterone receptor (PR) status, and first course treatment, we did not observe significant associations between expression of CYP27A1 or CYP7B1 and mortality across all cases. However, in subgroup analyses within major racial/ethnic groups (Caucasian, Japanese, and Native Hawaiian) we observed a significant negative association for CYP7B1 expression for both breast cancer-specific (HR=0.057, 95% CI: 0.012-0.264) and overall mortality (HR=0.119, 95% CI: 0.028-0.509) among Native Hawaiian women, but not among Caucasian or Japanese women. This is the first report to demonstrate racial/ethnic differences in the association between the levels of these cholesterol regulating enzymes in breast tumors and survival in a multiethnic population of breast cancer patients. Citation Format: Lenora WM Loo, Yurii B Shvetsov, Iona Cheng, Brenda Y Hernandez. The association between 27-hydroxycholesterol metabolizing enzym