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Impact of 27-hydroxylase (CYP27A1) and 27-hydroxycholesterol in breast cancer

Kimbung, Siker LU ; Chang, Ching-Yi; Bendahl, Pär-Ola LU ; Dubois, Laura; Thompson, J Will; McDonnell, Donald P and Borgquist, Signe LU (2017) In Endocrine-Related Cancer 24(7). p.339-349
Abstract

The impact of systemic 27-hydroxycholesterol (27HC) and intratumoral CYP27A1 expression on pathobiology and clinical response to statins in breast cancer needs clarification. 27HC is an oxysterol produced from cholesterol by the monooxygenase CYP27A1, which regulates intracellular cholesterol homeostasis. 27HC also acts as an endogenous selective estrogen receptor (ER) modulator capable of increasing breast cancer growth and metastasis. 27HC levels can be modulated by statins or direct inhibition of CYP27A1, thereby attenuating its pro-tumorigenic activities. Herein, the effect of statins on serum 27HC and tumor-specific CYP27A1 expression was evaluated in 42 breast cancer patients treated with atorvastatin within a phase II clinical... (More)

The impact of systemic 27-hydroxycholesterol (27HC) and intratumoral CYP27A1 expression on pathobiology and clinical response to statins in breast cancer needs clarification. 27HC is an oxysterol produced from cholesterol by the monooxygenase CYP27A1, which regulates intracellular cholesterol homeostasis. 27HC also acts as an endogenous selective estrogen receptor (ER) modulator capable of increasing breast cancer growth and metastasis. 27HC levels can be modulated by statins or direct inhibition of CYP27A1, thereby attenuating its pro-tumorigenic activities. Herein, the effect of statins on serum 27HC and tumor-specific CYP27A1 expression was evaluated in 42 breast cancer patients treated with atorvastatin within a phase II clinical trial. Further, the associations between CYP27A1 expression with other primary tumor pathological features and clinical outcomes were studied in two additional independent cohorts. Statin treatment effectively decreased serum 27HC and deregulated CYP27A1 expression in tumors. However, these changes were not associated with anti-proliferative responses to statin treatment. CYP27A1 was heterogeneously expressed among primary tumors, with high expression significantly associated with high tumor grade, ER negativity and basal-like subtype. High CYP27A1 expression was independently prognostic for longer recurrence-free and overall survival. Importantly, the beneficial effect of high CYP27A1 in ER-positive breast cancer seemed limited to women aged ≤50 years. These results establish a link between CYP27A1 and breast cancer pathobiology and prognosis and propose that the efficacy of statins in reducing serum lipids does not directly translate to anti-proliferative effects in tumors. Changes in other undetermined serum or tumor factors suggestively mediate the anti-proliferative effects of statins in breast cancer.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Endocrine-Related Cancer
volume
24
issue
7
pages
11 pages
publisher
Society for Endocrinology
external identifiers
  • wos:000404978400008
  • scopus:85027280701
ISSN
1479-6821
DOI
10.1530/ERC-16-0533
language
English
LU publication?
yes
id
71d7dd5a-cd43-40fa-b738-5a875562df7b
date added to LUP
2017-11-07 16:03:55
date last changed
2018-04-15 04:48:35
@article{71d7dd5a-cd43-40fa-b738-5a875562df7b,
  abstract     = {<p>The impact of systemic 27-hydroxycholesterol (27HC) and intratumoral CYP27A1 expression on pathobiology and clinical response to statins in breast cancer needs clarification. 27HC is an oxysterol produced from cholesterol by the monooxygenase CYP27A1, which regulates intracellular cholesterol homeostasis. 27HC also acts as an endogenous selective estrogen receptor (ER) modulator capable of increasing breast cancer growth and metastasis. 27HC levels can be modulated by statins or direct inhibition of CYP27A1, thereby attenuating its pro-tumorigenic activities. Herein, the effect of statins on serum 27HC and tumor-specific CYP27A1 expression was evaluated in 42 breast cancer patients treated with atorvastatin within a phase II clinical trial. Further, the associations between CYP27A1 expression with other primary tumor pathological features and clinical outcomes were studied in two additional independent cohorts. Statin treatment effectively decreased serum 27HC and deregulated CYP27A1 expression in tumors. However, these changes were not associated with anti-proliferative responses to statin treatment. CYP27A1 was heterogeneously expressed among primary tumors, with high expression significantly associated with high tumor grade, ER negativity and basal-like subtype. High CYP27A1 expression was independently prognostic for longer recurrence-free and overall survival. Importantly, the beneficial effect of high CYP27A1 in ER-positive breast cancer seemed limited to women aged ≤50 years. These results establish a link between CYP27A1 and breast cancer pathobiology and prognosis and propose that the efficacy of statins in reducing serum lipids does not directly translate to anti-proliferative effects in tumors. Changes in other undetermined serum or tumor factors suggestively mediate the anti-proliferative effects of statins in breast cancer.</p>},
  author       = {Kimbung, Siker and Chang, Ching-Yi and Bendahl, Pär-Ola and Dubois, Laura and Thompson, J Will and McDonnell, Donald P and Borgquist, Signe},
  issn         = {1479-6821},
  language     = {eng},
  number       = {7},
  pages        = {339--349},
  publisher    = {Society for Endocrinology},
  series       = {Endocrine-Related Cancer},
  title        = {Impact of 27-hydroxylase (CYP27A1) and 27-hydroxycholesterol in breast cancer},
  url          = {http://dx.doi.org/10.1530/ERC-16-0533},
  volume       = {24},
  year         = {2017},
}