Neuroligin 4X overexpression in human breast cancer is associated with poor relapse-free survival

Henderson, Henry J.; Karanam, Balasubramanyam; Samant, Rajeev S.; Vig, Komal; Singh, Shree R.; Yates, Clayton; Bedi, Deepa

doi:10.1371/journal.pone.0189662

Cited by 11 publications

(15 citation statements)

References 27 publications

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“…A number of these genes have been reported to be associated with other cancers [WWC3 (52,53), DOCK11 (54) and ARSD (55)]. In particular, NLGN4X expression was associated with survival in breast cancer (56). BGN expression was associated with proliferation in colon cancer (57) and poor prognosis in prostate cancer (58).…”

Section: Discussionmentioning

confidence: 99%

Molecular signatures of X chromosome inactivation and associations with clinical outcomes in epithelial ovarian cancer

Winham

Larson

Armasu

et al. 2018

Human Molecular Genetics

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X chromosome inactivation (XCI) is a key epigenetic gene expression regulatory process, which may play a role in women’s cancer. In particular tissues, some genes are known to escape XCI, yet patterns of XCI in ovarian cancer (OC) and their clinical associations are largely unknown. To examine XCI in OC, we integrated germline genotype with tumor copy number, gene expression and DNA methylation information from 99 OC patients. Approximately 10% of genes showed different XCI status (either escaping or being subject to XCI) compared with the studies of other tissues. Many of these genes are known oncogenes or tumor suppressors (e.g. DDX3X, TRAPPC2 and TCEANC). We also observed strong association between cis promoter DNA methylation and allele-specific expression imbalance (P = 2.0 × 10−10). Cluster analyses of the integrated data identified two molecular subgroups of OC patients representing those with regulated (N = 47) and dysregulated (N = 52) XCI. This XCI cluster membership was associated with expression of X inactive specific transcript (P = 0.002), a known driver of XCI, as well as age, grade, stage, tumor histology and extent of rl disease following surgical debulking. Patients with dysregulated XCI (N = 52) had shorter time to recurrence (HR = 2.34, P = 0.001) and overall survival time (HR = 1.87, P = 0.02) than those with regulated XCI, although results were attenuated after covariate adjustment. Similar findings were observed when restricted to high-grade serous tumors. We found evidence of a unique OC XCI profile, suggesting that XCI may play an important role in OC biology. Additional studies to examine somatic changes with paired tumor-normal tissue are needed.

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Section: Discussionmentioning

confidence: 99%

Molecular signatures of X chromosome inactivation and associations with clinical outcomes in epithelial ovarian cancer

Winham

Larson

Armasu

et al. 2018

Human Molecular Genetics

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“…Three most significantly downregulated genes were COCH (log2FC = −3.1, q = 3.7 × 10 −146 ) encoding a highly conserved protein with GO (Gene Ontology) annotated molecular functions in collagen binding, NLGN4X (log2FC = −2.9, q = 5.2 × 10 −83 ), a cell adhesion molecule with function in protein–protein interactions at synapses but also with altered expression in breast cancer, and KIF7 (log2FC = −2.0, q = 3.0 × 10 −37 ), involved in regulation of microtubular dynamics and essential for hedgehog signaling (Supporting Information Table S2). Other downregulated genes included DENND2D , guanine nucleotide exchange factor (GEF) previously linked to suppression of non‐small cell lung cancer proliferation and tumorigenicity, and SPARC , involved in extracellular matrix synthesis and promotion of changes to cell shape that can enhance tumor cell invasion.…”

Section: Resultsmentioning

confidence: 99%

Tumor suppressor MCPH1 regulates gene expression profiles related to malignant conversion and chromosomal assembly

Tervasmäki

Mantere

Eshraghi

et al. 2019

Intl Journal of Cancer

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Strong inherited predisposition to breast cancer is estimated to cause about 5–10% of all breast cancer cases. As the known susceptibility genes, such as BRCA1 and BRCA2, explain only a fraction of this, additional predisposing genes and related biological mechanisms are actively being searched for. We have recently identified a recurrent MCPH1 germline mutation, p.Arg304ValfsTer3, as a breast cancer susceptibility allele. MCPH1 encodes a multifunctional protein involved in maintenance of genomic integrity and it is also somatically altered in various cancer types, including breast cancer. Additionally, biallelic MCPH1 mutations are causative for microcephaly and at cellular level premature chromosome condensation. To study the molecular mechanisms leading to cancer predisposition and malignant conversion, here we have modeled the effect of MCPH1 p.Arg304ValfsTer3 mutation using gene‐edited MCF10A breast epithelial cells. As a complementary approach, we also sought for additional potential cancer driver mutations in MCPH1 p.Arg304ValfsTer3 carrier breast tumors. We show that mutated MCPH1 de‐regulates transcriptional programs related to invasion and metastasis and leads to downregulation of histone genes. These global transcriptional changes are mirrored by significantly increased migration and invasion potential of the cells as well as abnormal chromosomal condensation both before and after mitosis. These findings provide novel molecular insights to MCPH1 tumor suppressor functions and establish a role in regulation of transcriptional programs related to malignant conversion and chromosomal assembly. The MCPH1 p.Arg304ValfsTer3 carrier breast tumors showed recurrent tumor suppressor gene TP53 mutations, which were also significantly over‐represented in breast tumors with somatically inactivated MCPH1.

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“…Neuroligins constitute a family of neuronal transmembrane synaptic proteins whose structural and biochemical characteristics are indicative of a role in heterotypic cell adhesion. The neuroligin gene family consists of five members (NLGN1 at 3q26, NLGN2 at 17p13, NLGN3 at Xq13, NLGN4 at Xp22, and NLGN4Y at Yq11) [18,39]. Their large extracellular N-terminal domain is homologous to serine esterases.…”

Section: Introductionmentioning

confidence: 99%

“…Our previous the first study to link the expression of neuronal cell adhesion molecules, neuroligins, in breast cancer [18]. NLGN4X plays a vital role in enhancing tumorigenesis and aggressiveness of breast cancer with MCPH1 loss/mutation [35].…”

Section: Introductionmentioning

confidence: 99%

Loss of Neuroligin 4X Induces An Intrinsic Innate Immune Response in TNBC

Yirsaw

Khodary

Elhussin

et al. 2021

Preprint

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Background Immune checkpoint blockade therapies, which act on T cell inhibitory receptors, including CTLA-4 and PD-1, induce durable responses across diverse cancers. However, most patients do not respond to these therapies, and initially responsive cancers may relapse. Identifying molecular mechanisms that influence therapeutic responses and resistance is critical to realize the full therapeutic potential of immune checkpoint inhibitors. The presence of immune infiltrates in the tumor microenvironment is associated with positive outcomes in breast cancer, specifically in triple-negative breast cancer (TNBC). The underlying mechanisms driving this response are unclear. We have previously identified Neuroligin 4X (NLGN4X) as a protein expressed in TNBC.Methods Bioinformatic analysis was used for pathway analysis of TCGA TNBC patient dataset. Immunohistochemistry was performed on breast cancer tissue microarray for NLGN4X protein expression. RNA-seq was performed on MDA-MB-231 breast cancer cells for differential gene expression upon gene knockdown. Cytokine array, western blot, cell adhesion array and Nanostring was performed to determine the role of NLGN4X in TNBC.Results In this study, we report that NLGN4X expression is lost in breast cancer with lymph node metastasis. Its expression negatively correlates with immune markers in vitro, The Cancer Genome Atlas (TCGA) TNBC patient dataset, and metastatic breast cancer tissues. RNA-seq analysis of the MDA-MB-231 breast cancer cell line, silenced for NLGN4X by siRNA showed more than 500 differentially regulated genes. GSEA analysis of these genes revealed upregulation of interferon signaling pathway, cytokine signaling, and downregulation of cholesterol metabolism and lipid metabolism pathways. NLGN4X knockdown induced loss of cell adhesion, epithelial to mesenchymal transition (EMT), and MAVS-IRF7 signaling in breast cancer cells. Interestingly, analysis of the TCGA dataset of 104 TNBC patients also showed interferon signaling (IFN) as one of the significant pathways downregulated in TNBC patients expressing NLGN4X.Conclusion Loss of NLGN4X leads to innate immune activation in breast cancer and coincides with an aggressive phenotype of cancer. This study identifies the role of NLGN4X in regulating interferon signaling and immune microenvironment in TNBC.

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Neuroligin 4X overexpression in human breast cancer is associated with poor relapse-free survival

Cited by 11 publications

References 27 publications

Molecular signatures of X chromosome inactivation and associations with clinical outcomes in epithelial ovarian cancer

Molecular signatures of X chromosome inactivation and associations with clinical outcomes in epithelial ovarian cancer

Tumor suppressor MCPH1 regulates gene expression profiles related to malignant conversion and chromosomal assembly

Loss of Neuroligin 4X Induces An Intrinsic Innate Immune Response in TNBC

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