Abstract:
:Membrane overexpression of the receptor tyrosine kinase ErbB-2 (MErbB-2) accounts for a clinically aggressive breast cancer (BC) subtype (ErbB-2-positive) with increased incidence of metastases. We and others demonstrated that nuclear ErbB-2 (NErbB-2) also plays a key role in BC and is a poor prognostic factor in ErbB-2-positive tumors. The signal transducer and activator of transcription 3 (Stat3), another player in BC, has been recognized as a downstream mediator of MErbB-2 action in BC metastasis. Here, we revealed an unanticipated novel direction of the ErbB-2 and Stat3 interaction underlying BC metastasis. We found that Stat3 binds to its response elements (GAS) at the ErbB-2 promoter to upregulate ErbB-2 transcription in metastatic, ErbB-2-positive BC. We validated these results in several BC subtypes displaying metastatic and non-metastatic ability, highlighting Stat3 general role as upstream regulator of ErbB-2 expression in BC. Moreover, we showed that Stat3 co-opts NErbB-2 function by recruiting ErbB-2 as its coactivator at the GAS sites in the promoter of microRNA-21 (miR-21), a metastasis-promoting microRNA (miRNA). Using an ErbB-2 nuclear localization domain mutant and a constitutively activated ErbB-2 variant, we found that NErbB-2 role as a Stat3 coactivator and also its direct role as transcription factor upregulate miR-21 in BC. This reveals a novel function of NErbB-2 as a regulator of miRNAs expression. Increased levels of miR-21, in turn, downregulate the expression of the metastasis-suppressor protein programmed cell death 4 (PDCD4), a validated miR-21 target. Using an in vivo model of metastatic ErbB-2-postive BC, in which we silenced Stat3 and reconstituted ErbB-2 or miR-21 expression, we showed that both are downstream mediators of Stat3-driven metastasis. Supporting the clinical relevance of our results, we found an inverse correlation between ErbB-2/Stat3 nuclear co-expression and PDCD4 expression in ErbB-2-positive primary invasive BCs. Our findings identify Stat3 and NErbB-2 as novel therapeutic targets to inhibit ErbB-2-positive BC metastasis.
journal_name
Oncogenejournal_title
Oncogeneauthors
Venturutti L,Romero LV,Urtreger AJ,Chervo MF,Cordo Russo RI,Mercogliano MF,Inurrigarro G,Pereyra MG,Proietti CJ,Izzo F,Díaz Flaqué MC,Sundblad V,Roa JC,Guzmán P,Bal de Kier Joffé ED,Charreau EH,Schillaci R,Elizalde PVdoi
10.1038/onc.2015.281subject
Has Abstractpub_date
2016-04-28 00:00:00pages
2208-22issue
17eissn
0950-9232issn
1476-5594pii
onc2015281journal_volume
35pub_type
杂志文章相关文献
ONCOGENE文献大全abstract::We have cloned a novel quail cDNA with strong homology to the pim family of proto-oncogenes. The deduced amino acid (aa) sequence of the cDNA, named qpim, is more closely related to Xenopus Pim and to the recently identified rat Pim-3 than to human or rodent Pim-1 or Pim-2. The protein encoded by the qpim cDNA can aut...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1203355
更新日期:2000-02-24 00:00:00
abstract::Mdm2, a regulator of the p53 tumor suppressor, is frequently overexpressed in lymphomas, including lymphomas that have inactivated p53. However, the biological consequences of Mdm2 overexpression in lymphocytes are not fully resolved. Here, we report that increased expression of Mdm2 in B cells augmented proliferation...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1210788
更新日期:2008-03-06 00:00:00
abstract::Pilocytic astrocytomas (PAs, WHO grade I) are the most common brain tumors in the pediatric and adolescent population, accounting for approximately one-fifth of central nervous system tumors. Because few consistent molecular alterations have been identified in PAs compared to higher grade gliomas, we performed array c...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/onc.2008.110
更新日期:2008-08-07 00:00:00
abstract::Although cyclin D1 is overexpressed in a significant number of human cancers, overexpression alone is insufficient to promote tumorigenesis. In vitro studies have revealed that inhibition of cyclin D1 nuclear export unmasks its neoplastic potential. Cyclin D1 nuclear export depends upon phosphorylation of a C-terminal...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1209644
更新日期:2006-10-12 00:00:00
abstract::Somatostatin receptors (sst1-5) are present in different types of tumors, where they inhibit key cellular processes such as proliferation and invasion. Although ssts are densely expressed in breast cancer, especially sst2, their role and therapeutic potential remain uncertain. Recently, we identified a new truncated s...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/onc.2011.389
更新日期:2012-04-19 00:00:00
abstract::In order to elucidate the molecular mechanism(s) for BCL6 translocation, we identified translocational partner genes by subjecting clinical biopsy samples from patients with non-Hodgkin's lymphoma to 5'-rapid amplification of cDNA ends (5'-RACE). Sequence analysis of the 5'-RACE product revealed that the BCL6 gene was...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1203293
更新日期:1999-12-23 00:00:00
abstract::Epigenetic regulations play crucial roles in leukemogenesis and leukemia progression. SUV39H1 is the dominant H3K9 methyltransferase in the hematopoietic system, and its expression declines with aging. However, the role of SUV39H1 via its-mediated repressive modification H3K9me3 in leukemogenesis/leukemia progression ...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/s41388-020-01495-6
更新日期:2020-12-01 00:00:00
abstract::Junctional adhesion molecule-A (JAM-A) is a membranous cell-cell adhesion protein involved in tight-junction formation in epithelial and endothelial cells. Its overexpression in breast tumors has recently been linked with increased risk of metastasis. We sought to identify if JAM-A overexpression was associated with s...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/onc.2012.276
更新日期:2013-05-30 00:00:00
abstract::Resistance to anti-HER2 (human epithelial growth factor receptor 2) trastuzumab therapy occurs commonly in HER2-positive breast cancer and involves overactivation of HER2 and/or AKT1. Using the model of trastuzumab-sensitive or trastuzumab-resistant HER2-positive cells with wild-type PTEN, negative regulator of AKT1, ...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/onc.2009.422
更新日期:2010-03-04 00:00:00
abstract::In previous studies we changed five conserved amino acid residues in the catalytic domain of the yeast Ras-specific guanine nucleotide exchange factor CDC25GEF (Park et al., 1994). One of the substitutions (R1489E) resulted in a molecule which could bind Ras but was catalytically inactive. These observations suggested...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1200893
更新日期:1997-02-20 00:00:00
abstract::CD44 is a transmembrane glycoprotein known to bind hyaluronic acid (HA) in its extracellular domain and to contain at least one ankyrin-binding site in its cytoplasmic domain. In this study we have examined CD44 expression in a mouse fibroblast cell line transfected with the pl85(neu) oncogene cDNA. The results of RT-...
journal_title:Oncogene
pub_type: 杂志文章
doi:
更新日期:1996-06-06 00:00:00
abstract::Prevention and treatment options for hepatocellular carcinoma (HCC) are presently limited, underscoring the necessity for further elucidating molecular mechanisms underlying HCC development and identifying new prevention and therapeutic targets. Here, we demonstrate a unique protumorigenic niche in the livers of Ncoa5...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/s41388-020-1256-x
更新日期:2020-05-01 00:00:00
abstract::Cancer-Associated Fibroblasts (CAFs) are the most prominent stromal cell type in breast tumors. CAFs promote tumor growth and metastasis by multiple mechanisms, including by mediating tumor-promoting inflammation. Immune modulation in the tumor microenvironment plays a central role in determining disease outcome. Howe...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/onc.2017.65
更新日期:2017-08-01 00:00:00
abstract::Expression of polyomavirus middle-T antigen (middle-T) is involved in the formation of various tumors in vivo, e.g. hemangiomas and mammary gland tumors. Several genes have been shown to be activated in middle-T-expressing cells, but the underlying mechanisms have only been partially elucidated. Among the genes regula...
journal_title:Oncogene
pub_type: 杂志文章
doi:
更新日期:1995-12-07 00:00:00
abstract::xCT, the functional subunit of the cystine/glutamate transporter xc- system, plays a critical role in the maintenance of intracellular glutathione and redox balance. Disruption of xCT significantly inhibits the growth of a variety of carcinomas, including lymphoma, glioma, prostate and breast cancer. However, the role...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/onc.2008.414
更新日期:2009-01-29 00:00:00
abstract::The hyperactivated Wnt/β-catenin signaling acts as a switch to induce epithelial to mesenchymal transition and promote colorectal cancer. However, due to its essential role in gut homeostasis, therapeutic targeting of this pathway has proven challenging. Additionally, IL-6/Stat-3 signaling, activated by microbial tran...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/onc.2017.259
更新日期:2017-11-23 00:00:00
abstract::Biomarkers that predict disease progression might assist the development of better therapeutic strategies for aggressive cancers, such as ovarian cancer. Here, we investigated the role of collagen type XI alpha 1 (COL11A1) in cell invasiveness and tumor formation and the prognostic impact of COL11A1 expression in ovar...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/onc.2013.307
更新日期:2014-06-26 00:00:00
abstract::We have compared the DNase I hypersensitivity of the regulatory region of two estrogen-regulated genes, pS2 and cathepsin D in hormone-dependent and -independent breast carcinoma cell lines. This strategy allowed the identification of two important control regions, one in pS2 and the other in cathepsin D genes. In the...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1202317
更新日期:1999-01-14 00:00:00
abstract::Hepatocellular carcinoma (HCC) is the fifth leading cause of cancer-related mortality in the United States. Exploring the mechanism of HCC and identifying ideal targets is critical. In the present study, we demonstrated metabolism dysfunction might be a key diver for the development of HCC. The mitochondrial amidoxime...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/s41388-020-01417-6
更新日期:2020-09-01 00:00:00
abstract::Cyclooxygenase-2 (COX-2), the rate-limiting enzyme in the synthesis of prostaglandins, promotes the development of colorectal cancer, and is a key molecular target of non-steroidal anti-inflammatory drugs, compounds that reduce the relative risk of developing colon cancer. In this study, we showed that interferon gamm...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1210015
更新日期:2007-03-29 00:00:00
abstract::Parathyroid hormone-related protein (PTHrP) is a critical regulator of bone resorption and augments osteolysis in skeletal malignancies. Here we report that the mature PTHrP1-36 hormone is processed by matrix metalloproteinases to yield a stable product, PTHrP1-17. PTHrP1-17 retains the ability to signal through PTH1R...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/onc.2017.70
更新日期:2017-08-01 00:00:00
abstract::In contrast to other cell cycle inhibitors, the tumor suppressor p16Ink4a is not detectable or expressed at very low levels in embryonic and adult mouse tissues, and therefore it has often been considered as a specialized checkpoint protein that does not participate in the control of normal cell cycle progression. How...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1209437
更新日期:2006-07-06 00:00:00
abstract::Melanoma is the most aggressive form of skin cancer and is notoriously resistant to all current modalities of cancer therapy. A large set of genetic, functional and biochemical studies suggest that melanoma cells become 'bullet proof' against a variety of chemotherapeutic drugs by exploiting their intrinsic resistance...
journal_title:Oncogene
pub_type: 杂志文章,评审
doi:10.1038/sj.onc.1206454
更新日期:2003-05-19 00:00:00
abstract::Cellular adhesion to extracellular matrix is a central phenomenon for the maintenance of tissue integrity and cellular movement. Collectively, these processes are regulated by a fine-tuned balance between the formation and loosening of adhesive contacts, a process involving integrins, and the elevation and diminution ...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1210883
更新日期:2008-04-10 00:00:00
abstract::A hallmark of plasma cells is the expression of syndecan-1, which has major functions in epithelial cells, in particular as the coreceptor of heparin-binding growth factors. We previously found that heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a growth factor for malignant plasma cells. As am...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1208536
更新日期:2005-05-12 00:00:00
abstract::Poor-prognosis oestrogen receptor-positive breast cancer is characterised by the presence of high-level focal amplifications. We utilised a focused small interfering RNA screen in 14 breast cancer cell lines to define genes that were pathogenic in three genomic regions focally amplified in oestrogen receptor-positive ...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/onc.2013.202
更新日期:2014-05-08 00:00:00
abstract::Receptor tyrosine kinases (RTKs) control proliferation and differentiation through their ability to bind and/or phosphorylate intracellular substrates. The repertoire of substrates recruited by different RTK is largely overlapping. It is not clear, therefore, how a cell distinguishes among signals originating from dif...
journal_title:Oncogene
pub_type: 杂志文章
doi:
更新日期:1995-09-21 00:00:00
abstract::TFAP2C/AP-2γ influences development of the mammary gland and regulates patterns of gene expression in luminal and HER2-amplified breast cancer. The roles of TFAP2C in mammary gland tumorigenesis and in pathways critical to cancer progression remain poorly understood. To gain greater insight into oncogenic mechanisms r...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/onc.2015.59
更新日期:2015-12-10 00:00:00
abstract::Ultraviolet light (UV) induced DNA lesions efficiently block transcript elongation and induce the p53 response. Although p53 contributes to transcriptional activation of the p21waf1 and bax genes, accumulation of these proteins requires that these genes are free of UV induced pyrimidine dimers. We assessed the level o...
journal_title:Oncogene
pub_type: 杂志文章
doi:10.1038/sj.onc.1201963
更新日期:1998-08-06 00:00:00
abstract::The discovery of constitutive nuclear factor-κB (NF-κB) activation in Hodgkin's lymphoma tumor cells almost two decades ago was one of the first reports that directly connected deregulated NF-κB signaling to human cancer. Subsequent studies demonstrated that enhanced NF-κB signaling is a common hallmark of many lympho...
journal_title:Oncogene
pub_type: 杂志文章,评审
doi:10.1038/onc.2013.565
更新日期:2014-12-11 00:00:00