ERN1 and ALPK1 inhibit differentiation of bi-potential tumor-initiating cells in human breast cancer

Strietz, Juliane; Stepputtis, Stella S.; Preca, Bogdan‐Tiberius; Vannier, Corinne; Kim, Mihee M.; Castro, David J.; Au, Qingyan; Boerries, Melanie; Busch, Hauke; Aza-Blanc, Pedro; Heynen‐Genel, Susanne; Bronsert, Peter; Küster, Bernhard; Stickeler, Elmar; Brabletz, Thomas; Oshima, Robert G.; Maurer, Jochen

doi:10.18632/oncotarget.13086

Cited by 19 publications

(17 citation statements)

References 33 publications

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“…First, we identified a recurrent somatic missense ALPK1 mutation (p.V1092A) in the kinase domain of this alpha-kinase and demonstrated that this mutation can activate NF-κB signaling in cell reporter systems. Importantly, ALPK1 has previously been suggested to function as an oncogene 45 . Since kinases can be readily inhibited, this mutation represents a potential therapeutic target, which might be particularly advantageous in the advanced/metastatic setting, where effective treatments have not been identified.…”

Section: Discussionmentioning

confidence: 99%

ALPK1 hotspot mutation as a driver of human spiradenoma and spiradenocarcinoma

et al. 2019

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Spiradenoma and cylindroma are distinctive skin adnexal tumors with sweat gland differentiation and potential for malignant transformation and aggressive behaviour. We present the genomic analysis of 75 samples from 57 representative patients including 15 cylindromas, 17 spiradenomas, 2 cylindroma–spiradenoma hybrid tumors, and 24 low- and high-grade spiradenocarcinoma cases, together with morphologically benign precursor regions of these cancers. We reveal somatic or germline alterations of the CYLD gene in 15/15 cylindromas and 5/17 spiradenomas, yet only 2/24 spiradenocarcinomas. Notably, we find a recurrent missense mutation in the kinase domain of the ALPK1 gene in spiradenomas and spiradenocarcinomas, which is mutually exclusive from mutation of CYLD and can activate the NF-κB pathway in reporter assays. In addition, we show that high-grade spiradenocarcinomas carry loss-of-function TP53 mutations, while cylindromas may have disruptive mutations in DNMT3A . Thus, we reveal the genomic landscape of adnexal tumors and therapeutic targets.

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Section: Discussionmentioning

confidence: 99%

ALPK1 hotspot mutation as a driver of human spiradenoma and spiradenocarcinoma

et al. 2019

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“…19 In triple mutation breast cancer, ALPK1 cells can modulate tumorigenic ability in vivo and in vitro. 18 However, there has been little evidence for an association between ALPK1 expression and clinicopathologic signatures in OSCC. Here, higher expression of ALPK was demonstrated in OSCC than in nontumor tissue.…”

Section: Discussionmentioning

confidence: 99%

“…15 ALPK1 has also been shown to play a role in the immune response, acting as a critical mediator for interacting between Helicobacter pylori, gram-negative bacteria, and cellecell contact. 16,17 A recent study provided evidence that APLK1 plays an inhibitory role in the differentiation of breast cancer, 18 and ALPK1 mRNA expression is correlated with lung and colorectal cancer progression, 19 However, the association of ALPK1 expression with clinicopathologic features and the cancer progression of OSCC remains unclear.…”

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confidence: 99%

ALPK1 Expression Is Associated with Lymph Node Metastasis and Tumor Growth in Oral Squamous Cell Carcinoma Patients

Chen

Hua

Hsu

et al. 2019

The American Journal of Pathology

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Oral squamous cell carcinoma (OSCC) is the most common malignant cancer, with high mortality rates in advanced stages. Recent studies have shown that the expression of ALPK1 mRNA and its inhibitory differentiation function are associated with cancer progression. However, the expression and clinicopathologic features of ALPK1 in OSCC remain unexplored. Herein, the authors investigated the expression patterns of ALPK1 in 39 matched OSCC patients and examined the relationship between ALPK1 protein expression and clinicopathologic factors using immunohistochemical scores. Using Western blot analysis, ALPK1 expression was found to be significantly higher in tumor tissues than that in nontumor tissues. Through an immunoreactive scoring system, a significantly higher number of advanced-stage tumor size T4 and lymph node metastasis N2 exhibited higher ALPK1 expression levels than that exhibited by T1/T2/T3 tumors and N0/N1. In addition, ALPK1 protein expression was aberrant in malignant oral cancer cell lines compared with that in pre-malignant oral epithelial cells, whereas minimal expression was observed in normal oral epithelial cells. Knockdown of ALPK1 resulted in a significant reduction in cell growth, migration, and invasion capacity in vitro. Consequently, expression of N-cadherin and vimentin decreased in ALPK1-deficient cells. Thus, these results suggest that ALPK1 serves as a potential biomarker and target for OSCC development in late stages.

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“…Study by Jie Li and colleagues indicated that CBX4 was a critical regulator of tumor angiogenesis by governing HIF-1a protein [ 19 ]. Kanako Shinjo's findings demonstrated that expression CBX7 was associated with poor prognosis in ovarian clear cell adenocarcinoma via TRAIL-induced apoptotic pathway regulation [ 20 ]. However, the roles of distinct CBX members in contribution to tumorigenesis and development of BC are largely unknown.…”

Section: Introductionmentioning

confidence: 99%

Prognostic values of distinct CBX family members in breast cancer

et al. 2017

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Chromobox (CBX) family proteins are canonical components in polycomb repressive complexes 1 (PRC1), with epigenetic regulatory function and transcriptionally repressing target genes via chromatin modification. A plethora of studies have highlighted the function specifications among CBX family members in various cancer, including lung cancer, colon cancer and breast cancer. Nevertheless, the functions and prognostic roles of distinct CBX family members in breast cancer (BC) remain elusive. In this study, we reported the prognostic values of CBX family members in patients with BC through analysis of a series of databases, including CCLE, ONCOMINE, Xena Public Data Hubs, and Kaplan-Meier plotter. It was found that the mRNA expression of CBX family members were noticeably higher in BC than normal counterparts. CBX2 was highly expressed in Basal-like and HER-2 subtypes, while CBX4 and CBX7 expressions were enriched in Luminal A and Luminal B subtypes of BC. Survival analysis revealed that CBX1, CBX2 and CBX3 mRNA high expression was correlated to worsen relapse-free survival (RFS) for all BC patients, while CBX4, CBX5, CBX6 and CBX7 high expression was correlated to better RFS in this setting. Noteworthily, CBX1 and CBX2 were associated with chemoresistance whereas CBX7 was associated with tamoxifen sensitivity, as well as chemosensitivity in breast tumors. Therefore, we propose that CBX1, CBX2 and CBX7 are potential targets for BC treatment. The results might be beneficial for better understanding the complexity and heterogeneity in the molecular underpinning of BC, and to develop tools to more accurately predict the prognosis of patients with BC.

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ERN1 and ALPK1 inhibit differentiation of bi-potential tumor-initiating cells in human breast cancer

Cited by 19 publications

References 33 publications

ALPK1 hotspot mutation as a driver of human spiradenoma and spiradenocarcinoma

ALPK1 hotspot mutation as a driver of human spiradenoma and spiradenocarcinoma

ALPK1 Expression Is Associated with Lymph Node Metastasis and Tumor Growth in Oral Squamous Cell Carcinoma Patients

Prognostic values of distinct CBX family members in breast cancer

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