Screening for liver X receptor modulators: Where are we and for what use?

Buñay, Julio; Fouache, Allan; Trousson, Amalia; Joussineau, Cyrille de; Bouchareb, Erwan; Zhu, Zhekun; Kocer, Ayhan; Morel, Laurence; Baron, Silvère; Lobaccaro, Jean-Marc A.

doi:10.1111/bph.15286

Cited by 25 publications

(21 citation statements)

References 124 publications

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“…Some of our results are at odds with prior observations. We were unable to detect expression of XP_02430405X (previously termed a4 (Endo-Umeda et al, 2012)), in any cell lines or tissues, at RNA or protein level, including in HEPG2 or MCF7 cell lines that were previously shown to express this isoform (Bunay et al, 2020;Endo-Umeda et al, 2012). Intriguingly, a variant previously reported to be a5 (Bunay et al, 2020;Endo-Umeda et al, 2012) did not correspond to any of the 64 LXRa transcripts from NCBI nor any LXRa UNIPROT entries.…”

Section: Discussionmentioning

confidence: 62%

“…We were unable to detect expression of XP_02430405X (previously termed a4 (Endo-Umeda et al, 2012)), in any cell lines or tissues, at RNA or protein level, including in HEPG2 or MCF7 cell lines that were previously shown to express this isoform (Bunay et al, 2020;Endo-Umeda et al, 2012). Intriguingly, a variant previously reported to be a5 (Bunay et al, 2020;Endo-Umeda et al, 2012) did not correspond to any of the 64 LXRa transcripts from NCBI nor any LXRa UNIPROT entries. In this study (Endo-Umeda et al, 2012), the measurement of XP_02430405X and previously reported a5 relied on PCR primers that detected a retained intron between exon 6-7 and a retained intron between exon 7-8, respectively (see Figure S3).…”

Section: Discussionmentioning

confidence: 62%

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Characterization and prognostic value of LXR splice variants in triple-negative breast cancer

et al. 2021

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Activity of liver x receptor (LXR), the homeostatic regulator of cholesterol metabolism, is elevated in triple-negative breast cancer (BCa) relative to other BCa subtypes, driving drug resistance and metastatic gene signatures. The loci encoding LXRa and LXRb produce multiple alternatively spliced proteins, but the true range of variants and their relevance to cancer remain poorly defined. Here, we report seven LXR splice variants, three of which have not previously been reported and five that were prognostic for disease-free survival. Expression of full-length LXRa splice variants was associated with poor prognosis, consistent with a role as an oncogenic driver of triple-negative tumor pathophysiology. Contrary to this was the observation that high expression of truncated LXRa splice variants or any LXRb splice variant was associated with longer survival. These findings indicate that LXR isoform abundance is an important aspect of understanding the link between dysregulated cholesterol metabolism and cancer pathophysiology.

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Section: Discussionmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 62%

Characterization and prognostic value of LXR splice variants in triple-negative breast cancer

et al. 2021

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“…Some of our results are at odds with prior observations. We were unable to detect expression of XP_02430405X (previously termed a4 [16]), in any cell lines or tissues, at RNA or protein level, including in HEPG2 or MCF7 cell lines that were previously shown to express this isoform [16,33]. Intriguingly, a variant previously reported to be a5 [16,33] did not correspond to any of the 64 LXRa transcripts from NCBI, nor any LXRa UNIPROT entries (SF2A).…”

Section: Belorusova Et Al Reported Peptides Of Lxrα Comprising the H3 And Partial Part Of H5mentioning

confidence: 66%

“…We were unable to detect expression of XP_02430405X (previously termed a4 [16]), in any cell lines or tissues, at RNA or protein level, including in HEPG2 or MCF7 cell lines that were previously shown to express this isoform [16,33]. Intriguingly, a variant previously reported to be a5 [16,33] did not correspond to any of the 64 LXRa transcripts from NCBI, nor any LXRa UNIPROT entries (SF2A). In this study [16], the measurement of XP_02430405X and previously reported a5 relied on PCR primers that detected a retained intron between exon 6-7 and a retained intron between exon 7-8, respectively (SF2A).…”

Section: Belorusova Et Al Reported Peptides Of Lxrα Comprising the H3 And Partial Part Of H5mentioning

confidence: 66%

Comprehensive profiling of liver x receptor splicing in triple negative breast cancer reveals existence of novel splice variants that are prognostic for survival

Lianto

et al. 2021

Preprint

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The liver x receptors (LXR) alpha and beta are ligand-responsive transcription factors that link homeostatic control of lipid metabolism with cancer pathophysiology and prognosis. LXR activity is elevated in triple negative breast cancer relative to other breast cancer subtypes, driving gene signatures associated with drug resistance and metastasis. The loci encoding LXRα and LXRβ produce multiple alternatively spliced proteins, but the true range of variants and their relevance to cancer remain poorly defined. Seven splice variants of LXRα or LXRβ were detected. Three have not been recorded previously and five were prognostic. High expression of full length LXRα was associated with shorter disease-free survival but splice variants harbouring truncations of the ligand binding domain were prognostic for improved survival. All LXRa variants were associated with longer disease-free survival. Mechanistically, while full length LXRα positively correlated with target gene expression in primary samples, LXRβ was inversely correlated. We conclude that canonical LXRα function is an oncogenic driver of triple negative tumour pathophysiology that can be countered by high expression of truncated splice variants and/or full length LXRβ.

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“…Strategies for improving the efficacy and safety of these therapeutic drugs have been actively developed [109][110][111]. Statins can also be classified as anti-cancer agents that inhibit lipid raft-mediated Akt signalling [71,73,103,104].…”

Section: Therapeutic Approaches Targeting Lipid Raft Dynamics Through Primary Ciliamentioning

confidence: 99%

Primary cilia and lipid raft dynamics

et al. 2021

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Primary cilia, antenna-like structures of the plasma membrane, detect various extracellular cues and transduce signals into the cell to regulate a wide range of functions. Lipid rafts, plasma membrane microdomains enriched in cholesterol, sphingolipids and specific proteins, are also signalling hubs involved in a myriad of physiological functions. Although impairment of primary cilia and lipid rafts is associated with various diseases, the relationship between primary cilia and lipid rafts is poorly understood. Here, we review a newly discovered interaction between primary cilia and lipid raft dynamics that occurs during Akt signalling in adipogenesis. We also discuss the relationship between primary cilia and lipid raft-mediated Akt signalling in cancer biology. This review provides a novel perspective on primary cilia in the regulation of lipid raft dynamics.

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Screening for liver X receptor modulators: Where are we and for what use?

Cited by 25 publications

References 124 publications

Characterization and prognostic value of LXR splice variants in triple-negative breast cancer

Characterization and prognostic value of LXR splice variants in triple-negative breast cancer

Comprehensive profiling of liver x receptor splicing in triple negative breast cancer reveals existence of novel splice variants that are prognostic for survival

Primary cilia and lipid raft dynamics

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