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

Lianto, Priscilia; Hutchinson, Samantha A.; Moore, J. Bernadette; Hughes, Tom; Thorne, James L.

doi:10.1016/j.isci.2021.103212

Cited by 8 publications

(4 citation statements)

References 44 publications

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“…Thus, evaluating expression levels of both CLDN4 (input signal) and LXRβ (output signal) is required to predict distinct prognoses in TNBC cases. Along this line, clinicopathological analysis using expression levels of either CLDN4 [35][36][37] or LXRβ [51] does not seem to be enough to predict a prognosis in breast cancer, especially in TNBC. Since there is no valid medication for TNBC, it should also be worth noting that the CLDN4/LXRβ axis may be a promising therapeutic target for TNBC.…”

Section: Discussionmentioning

confidence: 99%

Claudin-4-adhesion signaling drives breast cancer metabolism and progression via liver X receptor β

et al. 2023

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Background Cell adhesion is indispensable for appropriate tissue architecture and function in multicellular organisms. Besides maintaining tissue integrity, cell adhesion molecules, including tight-junction proteins claudins (CLDNs), exhibit the signaling abilities to control a variety of physiological and pathological processes. However, it is still fragmentary how cell adhesion signaling accesses the nucleus and regulates gene expression. Methods By generating a number of knockout and rescued human breast cell lines and comparing their phenotypes, we determined whether and how CLDN4 affected breast cancer progression in vitro and in vivo. We also identified by RNA sequencing downstream genes whose expression was altered by CLDN4-adhesion signaling. Additionally, we analyzed by RT-qPCR the CLDN4-regulating genes by using a series of knockout and add-back cell lines. Moreover, by immunohistochemistry and semi-quantification, we verified the clinicopathological significance of CLDN4 and the nuclear receptor LXRβ (liver X receptor β) expression in breast cancer tissues from 187 patients. Results We uncovered that the CLDN4-adhesion signaling accelerated breast cancer metabolism and progression via LXRβ. The second extracellular domain and the carboxy-terminal Y197 of CLDN4 were required to activate Src-family kinases (SFKs) and the downstream AKT in breast cancer cells to promote their proliferation. Knockout and rescue experiments revealed that the CLDN4 signaling targets the AKT phosphorylation site S432 in LXRβ, leading to enhanced cell proliferation, migration, and tumor growth, as well as cholesterol homeostasis and fatty acid metabolism, in breast cancer cells. In addition, RT-qPCR analysis showed the CLDN4-regulated genes are classified into at least six groups according to distinct LXRβ- and LXRβS432-dependence. Furthermore, among triple-negative breast cancer subjects, the "CLDN4-high/LXRβ-high" and "CLDN4-low and/or LXRβ-low" groups appeared to exhibit poor outcomes and relatively favorable prognoses, respectively. Conclusions The identification of this machinery highlights a link between cell adhesion and transcription factor signalings to promote metabolic and progressive processes of malignant tumors and possibly to coordinate diverse physiological and pathological events.

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Section: Discussionmentioning

confidence: 99%

Claudin-4-adhesion signaling drives breast cancer metabolism and progression via liver X receptor β

et al. 2023

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“…In a study, the truncated LXRs splice variants were observed to be associated with better prognosis in TNBC. They have reported 7 LXRs splice variants, in which 3 LXRs splice variants are newly reported such as LXRα4 (has different AF1 region), LXRα5 (lacks AF1 and LBD regions in greater level), and LXRβ1(has different AF1 region) respectively ( Lianto et al, 2021 ). GW3965 downregulates the transcription factor E2F2 expression, and reduces its attachment to the target genes (mostly cis regions), and also downregulates the genes involved in the proliferation, replication, and cell cycle in BC in vitro ( Nguyen-Vu et al, 2013 ).…”

Section: Lxrs In Cancermentioning

confidence: 99%

Liver X Receptors (LXRs) in cancer-an Eagle’s view on molecular insights and therapeutic opportunities

Ramalingam,

Elangovan,

Mekala

et al. 2024

Front. Cell Dev. Biol.

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Cancer has become a serious health burden that results in high incidence and mortality rates every year, mainly due to various molecular alterations inside the cell. Liver X receptors (LXRs) dysregulation is one among them that plays a vital role in cholesterol metabolism, lipid metabolism and inflammation and also plays a crucial role in various diseases such as obesity, metabolic dysfunction-associated fatty liver disease (MAFLD), cardiovascular diseases, Type 2 diabetes, osteoporosis, and cancer. Studies report that the activation of LXRs inhibits cancer growth by inhibiting cellular proliferation, inducing apoptosis and autophagy, regulating cholesterol metabolism, various signalling pathways such as Wnt, and PI3K/AKT, modulating the expression levels of cell-cycle regulators, and promoting antitumor immunity inside the tumor microenvironment. In this review, we have discussed the role, structure, and functions of LXRs and also summarized their ligands along with their mechanism of action. In addition, the role of LXRs in various cancers, tumor immunity and tumor microenvironment (TME) along with the importance of precision medicine in LXR-targeted therapies has been discussed to emphasize the LXRs as potent targets for the development of novel cancer therapeutics.

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“…The activation of LXRs resists estrogen-induced cell proliferation by reducing estrogen receptor α at the mRNA and protein levels, but the exact mechanism remains to be further investigated [ 92 ]. Recently, a high expression of LXRs has been identified as a biomarker for a poor prognosis [ 93 , 94 , 95 ].…”

Section: Biological Functions and Mechanisms Of Lxrα In Diverse Cancersmentioning

confidence: 99%

Emerging Insights into Liver X Receptor α in the Tumorigenesis and Therapeutics of Human Cancers

Han,

Yuan,

Yan

et al. 2023

Biomolecules

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Liver X receptor α (LXRα), a member of the nuclear receptor superfamily, is identified as a protein activated by ligands that interacts with the promoters of specific genes. It regulates cholesterol, bile acid, and lipid metabolism in normal physiological processes, and it participates in the development of some related diseases. However, many studies have demonstrated that LXRα is also involved in regulating numerous human malignancies. Aberrant LXRα expression is emerging as a fundamental and pivotal factor in cancer cell proliferation, invasion, apoptosis, and metastasis. Herein, we outline the expression levels of LXRα between tumor tissues and normal tissues via the Oncomine and Tumor Immune Estimation Resource (TIMER) 2.0 databases; summarize emerging insights into the roles of LXRα in the development, progression, and treatment of different human cancers and their diversified mechanisms; and highlight that LXRα can be a biomarker and therapeutic target in diverse cancers.

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

Cited by 8 publications

References 44 publications

Claudin-4-adhesion signaling drives breast cancer metabolism and progression via liver X receptor β

Claudin-4-adhesion signaling drives breast cancer metabolism and progression via liver X receptor β

Liver X Receptors (LXRs) in cancer-an Eagle’s view on molecular insights and therapeutic opportunities

Emerging Insights into Liver X Receptor α in the Tumorigenesis and Therapeutics of Human Cancers

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