Feedback activation of STAT3 mediates trastuzumab resistance via upregulation of MUC1 and MUC4 expression

Li, Guangchao; Zhao, Likun; Li, Wei; Fan, Kexing; Qian, Weizhu; Hou, Sheng; Wang, Hao; Dai, Jing; Wei, Huafeng; Guo, Yajun

doi:10.18632/oncotarget.2135

Cited by 65 publications

(60 citation statements)

References 46 publications

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“…It has been documented that STAT3 hyperactivation was sufficient to confer trastuzumab resistance in HER-2-positive BC [28,29]. These studies suggest that pSTAT3 expression may be a critical point in signaling alteration promoting acquired trastuzumab resistance [28]. Collectively, the role of SHP-1 as a negative regulator led us to hypothesize that SHP-1 might decrease the expression of pSTAT3 via the STAT3 pathway.…”

Section: Discussionmentioning

confidence: 96%

“…It is known that protein tyrosine phosphatases (PTPs) have been reported to negatively regulate STAT3 activation [25][26][27]. It has been documented that STAT3 hyperactivation was sufficient to confer trastuzumab resistance in HER-2-positive BC [28,29]. These studies suggest that pSTAT3 expression may be a critical point in signaling alteration promoting acquired trastuzumab resistance [28].…”

Section: Discussionmentioning

confidence: 99%

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SHP-1 reverses trastuzumab resistance and migration in HER2-positive breast cancer cells through the stat3/p-stat3 pathway

Lei¹,

Li²,

Li³

et al. 2018

biomedicalresearch

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Decreased expression of Src homology region 2 domain containing protein tyrosine phosphatase 1 (SHP-1) was found in human breast cancer cell lines and primary breast cancers. As a candidate tumor suppressor gene, the role of SHP-1 in HER-2-positive breast cancer remains to be elucidated. The aim of the present study was to investigate the effects of upregulated SHP-1 expression in reversing trastuzumab resistance and migration by HER-2-positive breast cancer cells, potentially providing a new target to trastuzumab resistance in anti-HER2 therapy. Western blotting analysis was used to determine the expression levels of SHP-1 in trastuzumab-resistant cells transfected with a lentivirus vector expressing GFP-(control) or GFP-SHP-1 (experimental). MTT assay was used to determine changes in sensitivity to trastuzumab between two modified cell lines after overexpressing SHP-1. Clone formation and wound-healing assays were used to detect the capacity change in cell proliferation and migration. Western blot analysis was also used to examine the expressions of c-myc, cyclinD1, p-STAT3, STAT3, and MMP-9. Results from this study indicated that SHP-1 not only reduced cell proliferation and migration, but also significantly sensitized resistant cells to trastuzumab. Data also showed that SHP-1 restores sensitivity to trastuzumab in drug-resistant cell lines. Mechanistic analyses indicated that SHP-1 might target STAT3 to inactivate p-STAT3 and reduce expression of its downstream signaling pathway. In conclusion, results presented here suggest that targeting SHP-1 may represent a potential approach to re-sensitize previously resistant cells to trastuzumab treatment.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

SHP-1 reverses trastuzumab resistance and migration in HER2-positive breast cancer cells through the stat3/p-stat3 pathway

Lei¹,

Li²,

Li³

et al. 2018

biomedicalresearch

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“…Indeed, the hyperactivated STAT3 signal promotes the expression of MUC1 and MUC4 that mediate trastuzumab resistance via the maintenance of persistent HER2 activation and prevent the trastuzumab binding to HER2 [78]. In addition, IL6-STAT3 axis mediates the resistance to inhibitors of PI3K by inducing EMT and CSC expansion in human breast cancer cells [79].…”

Section: Role Of Stat3 In Cancermentioning

confidence: 99%

Investigational therapies targeting signal transducer and activator of transcription 3 for the treatment of cancer

Santoni

Massari

et al. 2015

Expert Opinion on Investigational Drugs

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Targeting STAT3 activation leads to the inhibition of tumor growth and metastasis both in vitro and in vivo without affecting normal cells; this suggests that STAT3 could be a valid molecular target for cancer therapy. Extensive clinical research is trying to find anti-STAT3 agents with high single-agent activity. The identification and development of novel drugs that can target deregulated STAT3 activation effectively is both a scientific and clinical challenge that needs to be addressed in the near future.

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“…It is reported that two single nucleotide polymorphisms (rs4072037 and rs2070803) in the MUC1 gene has been identified in gastric cancer patients and may have a prospective role in the stratification of high-risk subjects [171]. The overexpression of MUC1 and MUC4 also mediates resistance to the trastuzumab, a monoclonal antibody against HER-2/neu [172,173] siRNA to MUC1 was tested in trastuzumab drug resistance cells and a better response to the drug was seen in siRNA treated drug resistant cell when compared to control or junk siRNA treatment [174].…”

Section: Stomach Gastric Carcinomamentioning

confidence: 99%

Exploring the role and diversity of mucins in health and disease with special insight into non-communicable diseases

et al. 2015

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Mucins are major glycoprotein components of the mucus that coats the surfaces of cells lining the respiratory, digestive, gastrointestinal and urogenital tracts. They function to protect epithelial cells from infection, dehydration and physical or chemical injury, as well as to aid the passage of materials through a tract i.e., lubrication. They are also implicated in the pathogenesis of benign and malignant diseases of secretory epithelial cells. In Human there are two types of mucins, membrane-bound and secreted that are originated from mucous producing goblet cells localized in the epithelial cell layer or in mucous producing glands and encoded by MUC gene. Mucins belong to a heterogeneous family of high molecular weight proteins composed of a long peptidic chain with a large number of tandem repeats that form the so-called mucin domain. The molecular weight is generally high, ranging between 0.2 and 10 million Dalton and all mucins contain one or more domains which are highly glycosylated. The size and number of repeats vary between mucins and the genetic polymorphism represents number of repeats (VNTR polymorphisms), which means the size of individual mucins can differ substantially between individuals which can be used as markers. In human it is only MUC1 and MUC7 that have mucin domains with less than 40% serine and threonine which in turn could reduce number of PTS domains. Mucins can be considered as powerful two-edged sword, as its normal function protects from unwanted substances and organisms at an arm's length while, malfunction of mucus may be an important factor in human diseases. In this review we have unearthed the current status of different mucin proteins in understanding its role and function in various non-communicable diseases in human with special reference to its organ specific locations. The findings described in this review may be of direct relevance to the major research area in biomedicine with reference to mucin and mucin associated diseases.

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Feedback activation of STAT3 mediates trastuzumab resistance via upregulation of MUC1 and MUC4 expression

Cited by 65 publications

References 46 publications

SHP-1 reverses trastuzumab resistance and migration in HER2-positive breast cancer cells through the stat3/p-stat3 pathway

SHP-1 reverses trastuzumab resistance and migration in HER2-positive breast cancer cells through the stat3/p-stat3 pathway

Investigational therapies targeting signal transducer and activator of transcription 3 for the treatment of cancer

Exploring the role and diversity of mucins in health and disease with special insight into non-communicable diseases

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