Nuclear localisation of LASP-1 correlates with poor long-term survival in female breast cancer

Frietsch, Jochen J.; Grünewald, Thomas G.P.; Jasper, Shanese L.; Kämmerer, Ulrike; Herterich, Sabine; Kapp, Michaela; Hönig, Arnd; Butt, Elke

doi:10.1038/sj.bjc.6605685

Cited by 57 publications

(73 citation statements)

References 42 publications

(63 reference statements)

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“…However, compared with normal tissue, tumor cells display an increased rate of LASP1-positive nuclei (24,39), supporting the hypothesis that, next to its physiologic role as a scaffolding protein involved in cell motility, LASP1 may serve as a transcriptional cofactor involved in processes of cell proliferation and metastasis in malignant cells. Further studies will help to define the role of LASP1 in cancer development and metastasis.…”

Section: Discussionmentioning

confidence: 59%

“…Inactivating p53 mutations led to increased LASP1 expression and to a more aggressive hepatocellular carcinoma phenotype. Nevertheless, not all p53-mutated cell lines showed increased LASP1 expression (39). Interestingly, mRNA expression levels of p53, downstream intermediates and prominent target genes were not altered upon LASP1 knockdown in medulloblastoma cell lines (Supplementary Table S4 -6).…”

Section: Discussionmentioning

confidence: 93%

“…However, interdependence of prostate-derived Ets factor and LASP1 expression in breast cancer cell lines remains controversially discussed (39,41). None of the hallmark genes involved in metastatic cascades in breast cancer such as NM23, DLC1, NDRG1, KAI1, RHOGDI2, KISS1, and RKIP (reviewed in ref.…”

Section: Discussionmentioning

confidence: 99%

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Role of LIM and SH3 Protein 1 (LASP1) in the Metastatic Dissemination of Medulloblastoma

et al. 2010

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Medulloblastoma is the most common malignant pediatric brain tumor and is one of the leading causes of cancer-related mortality in children. Treatment failure mainly occurs in children harboring metastatic tumors, which typically carry an isochromosome 17 or gain of 17q, a common hallmark of intermediate and high-risk medulloblastoma. Through mRNA expression profiling, we identified LIM and SH3 protein 1 (LASP1) as one of the most upregulated genes on chromosome 17q in tumors with 17q gain. In an independent validation cohort of 101 medulloblastoma samples, the abundance of LASP1 mRNA was significantly associated with 17q gain, metastatic dissemination, and unfavorable outcome. LASP1 protein expression was analyzed by immunohistochemistry in a large cohort of patients (n = 207), and high protein expression levels were found to be strongly correlated with 17q gain, metastatic dissemination, and inferior overall and progression-free survival.In vitro experiments in medulloblastoma cell lines showed a strong reduction of cell migration, increased adhesion, and decreased proliferation upon LASP1 knockdown by small interfering RNA-mediated silencing, further indicating a functional role for LASP1 in the progression and metastatic dissemination of medulloblastoma.

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Section: Discussionmentioning

confidence: 59%

Section: Discussionmentioning

confidence: 93%

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Role of LIM and SH3 Protein 1 (LASP1) in the Metastatic Dissemination of Medulloblastoma

et al. 2010

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“…A predominant nuclear localization of LASP1 is observed in several cancer entities and was reported to correlate with worse long-time survival in breast cancer [18]. To test the subcellular LASP1 expression pattern in CML, Western blot analyses of cytosolic and nuclear fractions from K562, M07e, M07p210, BV173, Ba/F3 and Ba/F3p210 before and after nilotinib treatment were performed.…”

Section: Resultsmentioning

confidence: 99%

“…breast, ovarian, colon, prostate, liver, and bladder carcinoma as well as medulloblastoma [12-17]. Furthermore, LASP1 expression and nuclear localization significantly correlates with poor outcome of cancer patients [11, 12, 15, 18]. Silencing of LASP1 by RNA interference in various cell lines results in a strong inhibition of proliferation and migration with cell-cycle arrest in G2/M phase, whereas overexpression increased cancer cell proliferation and cell motility [13, 19].…”

Section: Introductionmentioning

confidence: 99%

LASP1 is a novel BCR-ABL substrate and a phosphorylation-dependent binding partner of CRKL in chronic myeloid leukemia

Frietsch

Kastner²,

Grünewald

et al. 2014

Oncotarget

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Chronic myeloid leukemia (CML) is characterized by a genomic translocation generating a permanently active BCR-ABL oncogene with a complex pattern of atypically tyrosine-phosphorylated proteins that drive the malignant phenotype of CML. Recently, the LIM and SH3 domain protein 1 (LASP1) was identified as a component of a six gene signature that is strongly predictive for disease progression and relapse in CML patients. However, the underlying mechanisms why LASP1 expression correlates with dismal outcome remained unresolved.Here, we identified LASP1 as a novel and overexpressed direct substrate of BCR-ABL in CML. We demonstrate that LASP1 is specifically phosphorylated by BCR-ABL at tyrosine-171 in CML patients, which is abolished by tyrosine kinase inhibitor therapy. Further studies revealed that LASP1 phosphorylation results in an association with CRKL – another specific BCR-ABL substrate and bona fide biomarker for BCR-ABL activity. pLASP1-Y171 binds to non-phosphorylated CRKL at its SH2 domain. Accordingly, the BCR-ABL-mediated pathophysiological hyper-phosphorylation of LASP1 in CML disrupts normal regulation of CRKL and LASP1, which likely has implications on downstream BCR-ABL signaling. Collectively, our results suggest that LASP1 phosphorylation might serve as an additional candidate biomarker for assessment of BCR-ABL activity and provide a first step toward a molecular understanding of LASP1 function in CML.

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Prenatal phthalate exposure and altered patterns of DNA methylation in cord blood

Solomon

Yousefi

Huen

et al. 2017

Environ and Mol Mutagen

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Epigenetic changes such as DNA methylation may be a molecular mechanism through which environmental exposures affect health. Phthalates are known endocrine disruptors with ubiquitous exposures in the general population including pregnant women, and they have been linked with a number of adverse health outcomes. We examined the association between in utero phthalate exposure and altered patterns of cord blood DNA methylation in 336 Mexican-American newborns. Concentrations of 11 phthalate metabolites were analyzed in maternal urine samples collected at 13 and 26 weeks gestation as a measure of fetal exposure. DNA methylation was assessed using the Infinium HumanMethylation 450K BeadChip adjusting for cord blood cell composition. To identify differentially methylated regions (DMRs) that may be more informative than individual CpG sites, we used two different approaches, DMRcate and comb-p. Regional assessment by both methods identified 27 distinct DMRs, the majority of which were in relation to multiple phthalate metabolites. Most of the significant DMRs (67%) were observed for later pregnancy (26 weeks gestation). Further, 51% of the significant DMRs were associated with the di-(2-ethylhexyl) phthalate metabolites. Five individual CpG sites were associated with phthalate metabolite concentrations after multiple comparisons adjustment (FDR), all showing hypermethylation. Genes with DMRs were involved in inflammatory response (IRAK4 and ESM1), cancer (BRCA1 and LASP1), endocrine function (CNPY1), and male fertility (IFT140, TESC, and PRDM8). These results on differential DNA methylation in newborns with prenatal phthalate exposure provide new insights and targets to explore mechanism of adverse effects of phthalates on human health. Environ. Mol. Mutagen. 58:398-410, 2017. © 2017 Wiley Periodicals, Inc.

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Nuclear localisation of LASP-1 correlates with poor long-term survival in female breast cancer

Cited by 57 publications

References 42 publications

Role of LIM and SH3 Protein 1 (LASP1) in the Metastatic Dissemination of Medulloblastoma

Role of LIM and SH3 Protein 1 (LASP1) in the Metastatic Dissemination of Medulloblastoma

LASP1 is a novel BCR-ABL substrate and a phosphorylation-dependent binding partner of CRKL in chronic myeloid leukemia

Prenatal phthalate exposure and altered patterns of DNA methylation in cord blood

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