CYP27A1 expression is associated with risk of late lethal estrogen receptor-positive breast cancer in postmenopausal patients

Abstract

Background 27-Hydroxycholesterol (27HC) stimulates estrogen receptor-positive (ER+) breast cancer (BC) progression. Inhibiting the sterol 27-hydroxylase (CYP27A1) abrogates these growth-promoting effects of 27HC in mice. However, the significance of CYP27A1 expression on BC biology and prognosis is unclear. Methods Intratumoral CYP27A1 expression in invasive BC was measured by immunohistochemistry in two Swedish population-based cohorts (n = 645 and n = 813, respectively). Cox proportional hazards models were used to evaluate the association between CYP27A1 expression and prognosis. Results CYP27A1 was highly expressed in less than 1/3 of the tumors. High CYP27A1 expression was more frequent among high-grade tumors lacking hormone receptor expression and with larger tumor sizes. Over a median of 12.2 years follow-up in cohort 1, high CYP27A1 expression was associated with impaired survival, specifically after 5 years from diagnosis among all patients [overall survival (OS), HRadjusted = 1.93, 95%CI = 1.26–2.97, P = 0.003; breast cancer-specific survival (BCSS), HRadjusted = 2.33, 95%CI = 1.28–4.23, P = 0.006] and among patients ≥ 55 years presenting with ER+ tumors [OS, HRadjusted = 1.99, 95%CI = 1.24–3.21, P = 0.004; BCSS, HRadjusted = 2.78, 95%CI = 1.41–5.51, P = 0.003]. Among all patients in cohort 2 (median follow-up of 7.0 years), CYP27A1 expression was significantly associated with shorter OS and RFS in univariable analyses across the full follow-up period. However after adjusting for tumor characteristics and treatments, the association with survival after 5 years from diagnosis was non-significant among all patients [OS, HRadjusted = 1.08, 95%CI = 0.05–2.35, P = 0.83 and RFS, HRadjusted = 1.22, 95%CI = 0.68–2.18, P = 0.50] as well as among patients ≥ 55 years presenting with ER+ tumors [OS, HRadjusted = 0.46 95% CI = 0.11–1.98, P = 0.30 and RFS, HRadjusted = 0.97 95% CI = 0.44–2.10, P = 0.93]. Conclusion CYP27A1 demonstrated great potentials as a biomarker of aggressive tumor biology and late lethal disease in postmenopausal patients with ER+ BC. Future studies should investigate if the benefits of prolonged endocrine therapy and cholesterol-lowering medication in BC are modified by CYP27A1 expression.

Role of 27-hydroxycholesterol and its metabolism in cancer progression: Human studies

“…Such a correlation appeared much stronger when only ER + tumors and patients ≤50 years of age were evaluated [18]. These findings could be considered as not really conflicting with those achieved by the same group later on, that on the contrary suggested an inverse correlation between CYP27A1 and RFS and OS parameters, but mainly in postmenopausal women bearing large size and high dedifferentiation grade breast carcinomas [17].…”

“…Relatively high CYP27A1 was detected in 20-30% of the cases, especially in tumors of Nottingham histological grade III. However, it should be noted that while in the first cohort of 645 women, where 90.2% were ≥55 years of age, a high CYP27A1 intra-tumoral level appeared to be a consistent indicator of adverse prognosis, in the patients of the second cohort bearing ER + cancer, with a much lower percent of postmenopausal women as to the first group, the inverse correlation between high CYP27A1 and survival resulted to be not statistically significant [17].…”

Vitamin D endocrine system in breast cancer

“…Nearly one third of breast cancer tumors expressed high CYP27A1 level. Moreover, the majority of them were high graded tumors, with larger size and without estrogen or progesterone receptors (Kimbung et al, 2020). According to the authors, breast cancer patients with high CYP27A1 displayed poorer overall survival and recurrence-free survival (Kimbung et al, 2020).…”

“…Nevertheless, there are several studies which investigated expression level of CYP27A1 in breast cancer patients. Kimbung and others (Kimbung et al, 2020) conducted a study relating to the immunohistochemical expression of CYP27A1 in breast cancer tumors. Nearly one third of breast cancer tumors expressed high CYP27A1 level.…”

“…Moreover, the majority of them were high graded tumors, with larger size and without estrogen or progesterone receptors (Kimbung et al, 2020). According to the authors, breast cancer patients with high CYP27A1 displayed poorer overall survival and recurrence-free survival (Kimbung et al, 2020). Another study revealed that an increased CYP27A1 level was predominantly detected in HER2 negative (HER2(-)) breast tumors in grade II with high Ki67 and p53 (Le Cornet et al, 2020).…”