STAT3, a Poor Survival Predicator, Is Associated with Lymph Node Metastasis from Breast Cancer

Chen, Yujuan; Wang, Jing; Wang, Xiaodong; Liu, Xuejuan; Li, Hongjiang; Lv, Qing; Zhu, Jingqiang; Wei, Bing; Tang, Ying

doi:10.4048/jbc.2013.16.1.40

Cited by 71 publications

(42 citation statements)

References 26 publications

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“…Additionally, the transcription and translation of the STAT3 target gene SOCS3 was attenuated by CK2 inhibition, supporting the functional consequences of STAT3 inhibition. These results have clinical significance, as STAT3 activation has been associated with late-stage, metastatic breast cancer [45, 46]. Thus, CK2 inhibition may be able to functionally replace inhibitors of STAT3, which have had difficulty reaching the clinic [47].…”

Section: Discussionmentioning

confidence: 99%

Therapeutic CK2 inhibition attenuates diverse prosurvival signaling cascades and decreases cell viability in human breast cancer cells

et al. 2014

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Breast cancer is the most common malignancy in women worldwide and remains a major cause of mortality, thus necessitating further therapeutic advancements. In breast cancer, numerous cell signaling pathways are aberrantly activated to produce the myriad phenotypes associated with malignancy; such pathways include the PI3K/Akt/mTOR, NF-κB and JAK/STAT cascades. These pathways are highly interconnected, but one prominent lateral enhancer of each is the remarkably promiscuous kinase CK2. CK2 expression has been shown to be elevated in cancer, thus implicating it in tumorigenesis through its effects on oncogenic signaling cascades. In this study, we identify aberrant expression of CK2 subunits in human breast samples from The Cancer Genome Atlas dataset. Additionally, two specific small molecule inhibitors of CK2, CX-4945 and TBB, were used to examine the role of CK2 in two human breast cancer cell lines, MDA-MB-231 and MCF-7 cells. We show that CK2 inhibition attenuates constitutive PI3K/Akt/mTOR, NF-κB and STAT3 activation and inducible NF-κB and JAK/STAT activation and downstream transcriptional activity. CX-4945 treatment caused a range of phenotypic changes in these cell lines, including decreased viability, cell cycle arrest, apoptosis and loss of migratory capacity. Overall, these results demonstrate the tremendous potential of CK2 as a clinical target in breast cancer.

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Section: Discussionmentioning

confidence: 99%

Therapeutic CK2 inhibition attenuates diverse prosurvival signaling cascades and decreases cell viability in human breast cancer cells

et al. 2014

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“…Recently silybin has shown to inhibit the phosphorylated signal transducer and activator of transcription protein-3 (pSTAT3; ref. 23), a marker of poor prognosis for many cancers, including breast (24). In a preclinical model of human gastric cancer, Wang and colleagues reported that the mechanism of action of silybin was related to a specific suppression of pSTAT3 and downregulation of STAT3 target genes, including Mcl-1, Bcl-xL, and survivin (25).…”

Section: Discussionmentioning

confidence: 99%

“…Tissue samples were analyzed in one batch for SIL and in two batches for TOT-SIL determination. Each batch included standards (range, 2-500 ng/g) and controls (6,24, and 400 ng/g). We used a subrogate matrix of pig muscle (Clinobs) for the preparation of standards and controls.…”

Section: Analysis Of Silybinmentioning

confidence: 99%

A Presurgical Study of Oral Silybin-Phosphatidylcholine in Patients with Early Breast Cancer

Lazzeroni

Guerrieri-Gonzaga

Gandini

et al. 2016

Cancer Prevention Research

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“…Constitutive STAT3 activation is frequently found in nearly all human cancers, and expression levels of p-STAT3(Y705) are often associated with poor prognosis (13)(14)(15). Mechanisms driving STAT3 activation in cancer are incompletely understood.…”

Section: Discussionmentioning

confidence: 99%

Frequent mutation of receptor protein tyrosine phosphatases provides a mechanism for STAT3 hyperactivation in head and neck cancer

Lui¹,

Peyser²,

Ng³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The underpinnings of STAT3 hyperphosphorylation resulting in enhanced signaling and cancer progression are incompletely understood. Loss-of-function mutations of enzymes that dephosphorylate STAT3, such as receptor protein tyrosine phosphatases, which are encoded by the PTPR gene family, represent a plausible mechanism of STAT3 hyperactivation. We analyzed whole exome sequencing (n = 374) and reverse-phase protein array data (n = 212) from head and neck squamous cell carcinomas (HNSCCs). PTPR mutations are most common and are associated with significantly increased phospho-STAT3 expression in HNSCC tumors. Expression of receptor-like protein tyrosine phosphatase T (PTPRT) mutant proteins induces STAT3 phosphorylation and cell survival, consistent with a "driver" phenotype. Computational modeling reveals functional consequences of PTPRT mutations on phospho-tyrosinesubstrate interactions. A high mutation rate (30%) of PTPRs was found in HNSCC and 14 other solid tumors, suggesting that PTPR alterations, in particular PTPRT mutations, may define a subset of patients where STAT3 pathway inhibitors hold particular promise as effective therapeutic agents.STAT3 activation | driver mutations | phosphatase mutations T yrosine phosphorylation regulates a multitude of cellular processes by coordinately activating and inactivating signaling proteins. Aberrations of protein tyrosine phosphorylation and signaling are a hallmark for oncogenic events found in most human cancers. The phosphorylation/dephosphorylation of tyrosine residues on signaling proteins is directly mediated by protein tyrosine kinases and phosphatases. Although many cellular factors are known to dynamically control the activity of these enzymes, genetic alterations of kinases and phosphatases in human cancers lead to perturbations in the levels of tyrosine phosphorylated proteins, uncontrolled cell growth, and tumor formation. Although activating mutations of tyrosine kinases have been extensively studied (1, 2), cancer-associated mutations of tyrosine phosphatases remain incompletely understood, partly due to the lack of comprehensive genomic analysis of these large arrays of phosphatases, as well as their largely unknown and often ambiguous actions in normal physiology and cancer biology.Among the 107 known protein tyrosine phosphatases, the receptor protein tyrosine phosphatases (RPTPs) represent the largest family of the human tyrosine phosphatome, comprising 21 family members (3). These RPTPs are believed to be crucial for the regulation of inter-as well as intracellular signaling due to the cell-surface localization of RPTPs. Selected members of the RPTP family have been reported to function as tumor suppressors, where gene mutation, deletion, or methylation may contribute to the cancer phenotype (3).STAT3 is an oncogene, and constitutive STAT3 activation is a hallmark of human cancers. Activating STAT3 mutations are rare in all cancers studied to date, including head and neck squamous cell carcinoma (HNSCC) (4). Although activating mutations of upst...

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STAT3, a Poor Survival Predicator, Is Associated with Lymph Node Metastasis from Breast Cancer

Cited by 71 publications

References 26 publications

Therapeutic CK2 inhibition attenuates diverse prosurvival signaling cascades and decreases cell viability in human breast cancer cells

Therapeutic CK2 inhibition attenuates diverse prosurvival signaling cascades and decreases cell viability in human breast cancer cells

A Presurgical Study of Oral Silybin-Phosphatidylcholine in Patients with Early Breast Cancer

Frequent mutation of receptor protein tyrosine phosphatases provides a mechanism for STAT3 hyperactivation in head and neck cancer

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