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

Kimbung, Siker LU ; Inasu, Maria LU ; Stålhammar, Tor ; Nodin, Björn LU ; Elebro, Karin LU ; Tryggvadottir, Helga LU ; Ygland Rödström, Maria ; Jirström, Karin LU orcid ; Isaksson, Karolin LU and Jernström, Helena LU , et al. (2020) In Breast Cancer Research 22(1).
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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
27-hydroxycholesterol, Breast cancer, Cholesterol, CYP27A1, Prognosis
in
Breast Cancer Research
volume
22
issue
1
article number
123
publisher
BioMed Central (BMC)
external identifiers
  • scopus:85095812762
  • pmid:33176848
ISSN
1465-5411
DOI
10.1186/s13058-020-01347-x
language
English
LU publication?
yes
id
d52790c6-237c-4a90-9cf5-5f21fdbea90e
date added to LUP
2020-12-09 15:16:54
date last changed
2024-04-17 20:40:23
@article{d52790c6-237c-4a90-9cf5-5f21fdbea90e,
  abstract     = {{<p>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), HR<sub>adjusted</sub> = 1.93, 95%CI = 1.26–2.97, P = 0.003; breast cancer-specific survival (BCSS), HR<sub>adjusted</sub> = 2.33, 95%CI = 1.28–4.23, P = 0.006] and among patients ≥ 55 years presenting with ER+ tumors [OS, HR<sub>adjusted</sub> = 1.99, 95%CI = 1.24–3.21, P = 0.004; BCSS, HR<sub>adjusted</sub> = 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, HR<sub>adjusted</sub> = 1.08, 95%CI = 0.05–2.35, P = 0.83 and RFS, HR<sub>adjusted</sub> = 1.22, 95%CI = 0.68–2.18, P = 0.50] as well as among patients ≥ 55 years presenting with ER+ tumors [OS, HR<sub>adjusted</sub> = 0.46 95% CI = 0.11–1.98, P = 0.30 and RFS, HR<sub>adjusted</sub> = 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.</p>}},
  author       = {{Kimbung, Siker and Inasu, Maria and Stålhammar, Tor and Nodin, Björn and Elebro, Karin and Tryggvadottir, Helga and Ygland Rödström, Maria and Jirström, Karin and Isaksson, Karolin and Jernström, Helena and Borgquist, Signe}},
  issn         = {{1465-5411}},
  keywords     = {{27-hydroxycholesterol; Breast cancer; Cholesterol; CYP27A1; Prognosis}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{BioMed Central (BMC)}},
  series       = {{Breast Cancer Research}},
  title        = {{CYP27A1 expression is associated with risk of late lethal estrogen receptor-positive breast cancer in postmenopausal patients}},
  url          = {{http://dx.doi.org/10.1186/s13058-020-01347-x}},
  doi          = {{10.1186/s13058-020-01347-x}},
  volume       = {{22}},
  year         = {{2020}},
}