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The effect of statin treatment on intratumoral cholesterol levels and LDL receptor expression : a window-of-opportunity breast cancer trial

Feldt, Maria LU ; Menard, Julien LU ; Rosendahl, Ann H LU ; Lettiero, Barbara LU ; Bendahl, Pär-Ola LU ; Belting, Mattias LU and Borgquist, Signe LU (2020) In Cancer & Metabolism 8(1).
Abstract

BACKGROUND: Deregulated lipid metabolism is common in cancer cells and the mevalonate pathway, which synthesizes cholesterol, is central in lipid metabolism. This study aimed to assess statin-induced changes of the intratumoral levels of cholesterol and the expression of the low-density lipoprotein receptor (LDLR) to enhance our understanding of the role of the mevalonate pathway in cancer cholesterol metabolism.

METHODS: This study is based on a phase II clinical trial designed as a window-of-opportunity trial including 50 breast cancer patients treated with 80 mg of atorvastatin/day for 2 weeks, between the time of diagnosis and breast surgery. Lipids were extracted from frozen tumor tissue sampled pre- and post-atorvastatin... (More)

BACKGROUND: Deregulated lipid metabolism is common in cancer cells and the mevalonate pathway, which synthesizes cholesterol, is central in lipid metabolism. This study aimed to assess statin-induced changes of the intratumoral levels of cholesterol and the expression of the low-density lipoprotein receptor (LDLR) to enhance our understanding of the role of the mevalonate pathway in cancer cholesterol metabolism.

METHODS: This study is based on a phase II clinical trial designed as a window-of-opportunity trial including 50 breast cancer patients treated with 80 mg of atorvastatin/day for 2 weeks, between the time of diagnosis and breast surgery. Lipids were extracted from frozen tumor tissue sampled pre- and post-atorvastatin treatment. Intratumoral cholesterol levels were measured using a fluorometric quantitation assay. LDLR expression was evaluated by immunohistochemistry on formalin-fixed paraffin-embedded tumor tissue. Paired blood samples pre- and post-atorvastatin were analyzed for circulating low-density lipoprotein (LDL), high-density lipoprotein (HDL), apolipoprotein A1, and apolipoprotein B. In vitro experiments on MCF-7 breast cancer cells treated with atorvastatin were performed for comparison on the cellular level.

RESULTS: In the trial, 42 patients completed all study parts. From the paired tumor tissue samples, assessment of the cholesterol levels was achievable for 14 tumors, and for the LDLR expression in 24 tumors. Following atorvastatin treatment, the expression of LDLR was significantly increased (P = 0.004), while the intratumoral levels of total cholesterol remained stable. A positive association between intratumoral cholesterol levels and tumor proliferation measured by Ki-67 expression was found. In agreement with the clinical findings, results from in vitro experiments showed no significant changes of the intracellular cholesterol levels after atorvastatin treatment while increased expression of the LDLR was found, although not reaching statistical significance.

CONCLUSIONS: This study shows an upregulation of LDLR and preserved intratumoral cholesterol levels in breast cancer patients treated with statins. Together with previous findings on the anti-proliferative effect of statins in breast cancer, the present data suggest a potential role for LDLR in the statin-induced regulation of breast cancer cell proliferation.

TRIAL REGISTRATION: The study has been registered at ClinicalTrials.gov (i.e., ID number: NCT00816244 , NIH), December 30, 2008.

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author
; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Breast cancer, Statin, Cholesterol, LDL receptor
in
Cancer & Metabolism
volume
8
issue
1
article number
25
pages
16 pages
external identifiers
  • pmid:33292612
ISSN
2049-3002
DOI
10.1186/s40170-020-00231-8
language
English
LU publication?
yes
id
a9b911ac-f3d0-449d-b1f9-8b1f3841037b
date added to LUP
2023-10-25 17:01:24
date last changed
2023-10-25 17:01:24
@article{a9b911ac-f3d0-449d-b1f9-8b1f3841037b,
  abstract     = {{<p>BACKGROUND: Deregulated lipid metabolism is common in cancer cells and the mevalonate pathway, which synthesizes cholesterol, is central in lipid metabolism. This study aimed to assess statin-induced changes of the intratumoral levels of cholesterol and the expression of the low-density lipoprotein receptor (LDLR) to enhance our understanding of the role of the mevalonate pathway in cancer cholesterol metabolism.</p><p>METHODS: This study is based on a phase II clinical trial designed as a window-of-opportunity trial including 50 breast cancer patients treated with 80 mg of atorvastatin/day for 2 weeks, between the time of diagnosis and breast surgery. Lipids were extracted from frozen tumor tissue sampled pre- and post-atorvastatin treatment. Intratumoral cholesterol levels were measured using a fluorometric quantitation assay. LDLR expression was evaluated by immunohistochemistry on formalin-fixed paraffin-embedded tumor tissue. Paired blood samples pre- and post-atorvastatin were analyzed for circulating low-density lipoprotein (LDL), high-density lipoprotein (HDL), apolipoprotein A1, and apolipoprotein B. In vitro experiments on MCF-7 breast cancer cells treated with atorvastatin were performed for comparison on the cellular level.</p><p>RESULTS: In the trial, 42 patients completed all study parts. From the paired tumor tissue samples, assessment of the cholesterol levels was achievable for 14 tumors, and for the LDLR expression in 24 tumors. Following atorvastatin treatment, the expression of LDLR was significantly increased (P = 0.004), while the intratumoral levels of total cholesterol remained stable. A positive association between intratumoral cholesterol levels and tumor proliferation measured by Ki-67 expression was found. In agreement with the clinical findings, results from in vitro experiments showed no significant changes of the intracellular cholesterol levels after atorvastatin treatment while increased expression of the LDLR was found, although not reaching statistical significance.</p><p>CONCLUSIONS: This study shows an upregulation of LDLR and preserved intratumoral cholesterol levels in breast cancer patients treated with statins. Together with previous findings on the anti-proliferative effect of statins in breast cancer, the present data suggest a potential role for LDLR in the statin-induced regulation of breast cancer cell proliferation.</p><p>TRIAL REGISTRATION: The study has been registered at ClinicalTrials.gov (i.e., ID number: NCT00816244 , NIH), December 30, 2008.</p>}},
  author       = {{Feldt, Maria and Menard, Julien and Rosendahl, Ann H and Lettiero, Barbara and Bendahl, Pär-Ola and Belting, Mattias and Borgquist, Signe}},
  issn         = {{2049-3002}},
  keywords     = {{Breast cancer; Statin; Cholesterol; LDL receptor}},
  language     = {{eng}},
  month        = {{11}},
  number       = {{1}},
  series       = {{Cancer & Metabolism}},
  title        = {{The effect of statin treatment on intratumoral cholesterol levels and LDL receptor expression : a window-of-opportunity breast cancer trial}},
  url          = {{http://dx.doi.org/10.1186/s40170-020-00231-8}},
  doi          = {{10.1186/s40170-020-00231-8}},
  volume       = {{8}},
  year         = {{2020}},
}