Cholesterol and breast cancer pathophysiology

Nelson, Erik R.; Chang, Ching Yi; McDonnell, Donald P.

doi:10.1016/j.tem.2014.10.001

Cited by 153 publications

(131 citation statements)

References 62 publications

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“…In terms of risk of onset, the role of cholesterol is unclear, further complicated as to whether total, LDL or HDL cholesterol impart risk [35, 66, 67]. Likewise, retrospective analysis of people on statin therapy indicates that these drugs might have conflicting roles in terms of breast cancer onset [68].…”

Section: Impact Of 27hc On the Progression Of Breast And Prostate Cmentioning

confidence: 99%

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27-Hydroxycholesterol, an endogenous selective estrogen receptor modulator

Nelson

2017

Maturitas

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Estrogen receptors (ERs) mediate the actions of the steroidal estrogens, and are important for the regulation of several physiological and pathophysiological processes, including reproduction, bone physiology, cardiovascular physiology and breast cancer. The unique pharmacology of the ERs allows for certain ligands, such as tamoxifen, to elicit tissue- and context-specific responses, ligands now referred to as selective estrogen receptor modulators (SERMs). Recently, the cholesterol metabolite 27-hydroxychoelsterol (27HC) has been defined as an endogenous SERM, with activities in atherosclerosis, osteoporosis, breast and prostate cancers, and neural degenerative diseases. Since 27HC concentrations closely mirror those of cholesterol, it is possible that 27HC mediates many of the biological effects of cholesterol. This paper provides an overview of ER pharmacology and summarizes the work to date implicating 27HC in various diseases. Wherever possible, we highlight clinical data in support of a role for 27HC in the diseases discussed.

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Section: Impact Of 27hc On the Progression Of Breast And Prostate Cmentioning

confidence: 99%

“…In murine models, a high fat, high cholesterol diet increases breast tumor growth and metastasis [35]. In a more controlled study, it was found that elevating only dietary cholesterol was sufficient to increase tumor growth in MMTV-PyMT mice [74].…”

Section: Impact Of 27hc On the Progression Of Breast And Prostate Cmentioning

confidence: 99%

27-Hydroxycholesterol, an endogenous selective estrogen receptor modulator

Nelson

2017

Maturitas

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“…Longer loop regulation is mediated by the liver X receptors (LXRs) which are intracellular receptors of the nuclear receptor superfamily, and which work to eliminate cholesterol through a feed-forward mechanism [74]. Specifically, certain precursors and metabolites of cholesterol such as oxysterols bind to and activate the LXRs, ultimately leading to decreased cellular uptake and increased efflux of cholesterol.…”

Section: Cholesterol Metabolismmentioning

confidence: 99%

The Contribution of Cholesterol and Its Metabolites to the Pathophysiology of Breast Cancer

Baek

Nelson

2016

HORM CANC

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As the most common cancer in women, one in eight will develop invasive breast cancer over their lifetime making it the second most common cause of cancer-related death among women. Of the many known risk factors for developing breast cancer, obesity stands out as prominent and modifiable. Interestingly, elevated cholesterol is highly associated with obesity, and has emerged as an independent risk factor for breast cancer onset and recurrence. This indicates that cholesterol also contributes to the breast cancer-pathogenicity of obesity. This review highlights our current understanding of the mechanisms by which cholesterol impacts breast cancer. Key preclinical studies have been highlighted, including discussion of homeostatic control of cholesterol levels, signaling by cholesterol metabolites through the estrogen receptors, cholesterol formation of lipid rafts and subsequent signaling, and the potential roles of cholesterol in creating a pro-inflammatory tumor microenvironment. Future directions and avenues for therapeutic exploitation are also considered.

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“…NR1H2/NR1H3 ligands secreted by tumor cells inhibit CCR7 expression on maturing dendritic cells, impairing immune-surveillance and favoring tumor growth [38]. In mouse breast-cancer models, 27-hydroxycholesterol augments ER-dependent mammary-tumor growth and increases NR1H2/NR1H3-dependent metastasis [39]. The two effects require conversion of cholesterol into 27-hydroxycholesterol by CYP27A1 [40].…”

Section: Lipid-sensorsmentioning

confidence: 99%

Lipid-sensors, enigmatic-orphan and orphan nuclear receptors as therapeutic targets in breast-cancer

et al. 2016

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Breast-cancer is heterogeneous and consists of various groups with different biological characteristics. Innovative pharmacological approaches accounting for this heterogeneity are needed. The forty eight human Nuclear-Hormone-Receptors are ligand-dependent transcription-factors and are classified into Endocrine-Receptors, Adopted-Orphan-Receptors (Lipid-sensors and Enigmatic-Orphans) and Orphan-receptors. Nuclear-Receptors represent ideal targets for the design/synthesis of pharmacological ligands. We provide an overview of the literature available on the expression and potential role played by Lipid-sensors, Enigmatic-Orphans and Orphan-Receptors in breast-cancer. The data are complemented by an analysis of the expression levels of each selected Nuclear-Receptor in the PAM50 breast-cancer groups, following re-elaboration of the data publicly available. The major aim is to support the idea that some of the Nuclear-Receptors represent largely unexploited therapeutic-targets in breast-cancer treatment/chemo-prevention. On the basis of our analysis, we conclude that the Lipid-Sensors, NR1C3, NR1H2 and NR1H3 are likely to be onco-suppressors in breast-cancer. The Enigmatic-Orphans, NR1F1 NR2A1 and NR3B3 as well as the Orphan-Receptors, NR0B1, NR0B2, NR1D1, NR2F1, NR2F2 and NR4A3 exert a similar action. These Nuclear-Receptors represent candidates for the development of therapeutic strategies aimed at increasing their expression or activating them in tumor cells. The group of Nuclear-Receptors endowed with potential oncogenic properties consists of the Lipid-Sensors, NR1C2 and NR1I2, the Enigmatic-Orphans, NR1F3, NR3B1 and NR5A2, as well as the Orphan-Receptors, NR2E1, NR2E3 and NR6A1. These oncogenic Nuclear-Receptors should be targeted with selective antagonists, reverse-agonists or agents/strategies capable of reducing their expression in breast-cancer cells.

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Cholesterol and breast cancer pathophysiology

Cited by 153 publications

References 62 publications

27-Hydroxycholesterol, an endogenous selective estrogen receptor modulator

27-Hydroxycholesterol, an endogenous selective estrogen receptor modulator

The Contribution of Cholesterol and Its Metabolites to the Pathophysiology of Breast Cancer

Lipid-sensors, enigmatic-orphan and orphan nuclear receptors as therapeutic targets in breast-cancer

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