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

Breast Cancer Res. 2020 Nov 11;22(1):123. doi: 10.1186/s13058-020-01347-x.

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.

Keywords: 27-hydroxycholesterol; Breast cancer; CYP27A1; Cholesterol; Prognosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Antineoplastic Agents, Hormonal / therapeutic use
  • Biomarkers, Tumor / analysis
  • Biomarkers, Tumor / metabolism*
  • Breast / pathology
  • Breast / surgery
  • Breast Neoplasms / diagnosis
  • Breast Neoplasms / mortality*
  • Breast Neoplasms / pathology
  • Breast Neoplasms / therapy
  • Chemotherapy, Adjuvant
  • Cholestanetriol 26-Monooxygenase / analysis
  • Cholestanetriol 26-Monooxygenase / metabolism*
  • Disease-Free Survival
  • Female
  • Follow-Up Studies
  • Humans
  • Hydroxycholesterols / metabolism
  • Immunohistochemistry
  • Kaplan-Meier Estimate
  • Mastectomy
  • Middle Aged
  • Neoplasm Grading
  • Neoplasm Recurrence, Local / epidemiology*
  • Neoplasm Recurrence, Local / pathology
  • Neoplasm Recurrence, Local / prevention & control
  • Postmenopause*
  • Prognosis
  • Receptors, Estrogen / analysis
  • Receptors, Estrogen / metabolism
  • Time Factors

Substances

  • Antineoplastic Agents, Hormonal
  • Biomarkers, Tumor
  • Hydroxycholesterols
  • Receptors, Estrogen
  • 27-hydroxycholesterol
  • CYP27A1 protein, human
  • Cholestanetriol 26-Monooxygenase