HRG-β1-driven ErbB3 signaling induces epithelial–mesenchymal transition in breast cancer cells

Kim, Jinkyoung; Jeong, Hoiseon; Lee, Youngseok; Kim, Chungyeul; Kim, Hankyeom; Kim, Aeree

doi:10.1186/1471-2407-13-383

Cited by 33 publications

(37 citation statements)

References 34 publications

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“…Studies using MCF-7 breast cancer cells ectopically overexpressing HRG, a model that mimics the scenario observed in human tumors, established prominent roles for the growth factor in motility and invasion. Furthermore, HRG promotes the secretion of matrix metalloproteases and confers metastatic properties on MCF-7 cells when inoculated into nude mice (10,(19)(20)(21)(22). Enhanced HRG/ErbB3 signaling has also been implicated in resistance to anticancer agents, including antiestrogens, ErbB tyrosine kinase inhibitors, and taxanes, and adaptive responses leading to drug resistance involve reprogramming of the kinome through reactivation of an HRG/ErbB3 axis (23)(24)(25)(26)(27)(28)(29).…”

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confidence: 99%

Heregulin/ErbB3 Signaling Enhances CXCR4-Driven Rac1 Activation and Breast Cancer Cell Motility via Hypoxia-Inducible Factor 1α

López‐Haber

Barrio-Real

Casado‐Medrano

et al. 2016

Molecular and Cellular Biology

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The growth factor heregulin (HRG), a ligand of ErbB3 and ErbB4 receptors, contributes to breast cancer development and the promotion of metastatic disease, and its expression in breast tumors has been associated with poor clinical outcome and resistance to therapy. In this study, we found that breast cancer cells exposed to sustained HRG treatment show markedly enhanced Rac1 activation and migratory activity in response to the CXCR4 ligand SDF-1/CXCL12, effects mediated by P-Rex1, a Rac-guanine nucleotide exchange factor (GEF) aberrantly expressed in breast cancer. Notably, HRG treatment upregulates surface expression levels of CXCR4, a G protein-coupled receptor (GPCR) implicated in breast cancer metastasis and an indicator of poor prognosis in breast cancer patients. A detailed mechanistic analysis revealed that CXCR4 upregulation and sensitization of the Rac response/motility by HRG are mediated by the transcription factor hypoxia-inducible factor 1␣ (HIF-1␣) via ErbB3 and independently of ErbB4. HRG caused prominent induction in the nuclear expression of HIF-1␣, which transcriptionally activates the CXCR4 gene via binding to a responsive element located in positions ؊1376 to ؊1372 in the CXCR4 promoter, as revealed by mutagenesis analysis and chromatin immunoprecipitation (ChIP). Our results uncovered a novel function for ErbB3 in enhancing breast cancer cell motility and sensitization of the P-Rex1/Rac1 pathway through HIF-1␣-mediated transcriptional induction of CXCR4. E rbB receptors are known to play key roles in cell proliferation, survival, and motility and have been widely implicated in the initiation and progression of cancer. Members of this family of transmembrane tyrosine kinases include epidermal growth factor receptors (EGFR) (ErbB1/HER1), ErbB2/HER2, ErbB3/HER3, and ErbB4/HER4. Ligands with distinctive affinities for ErbB receptors promote their homo-and heterodimerization, leading to stimulation of intrinsic tyrosine kinase activity; recruitment of adaptors and effectors to autophosphorylated tyrosine sites; and activation of key signaling cascades, namely, the phosphatidylinositol-3 kinase (PI3K)/Akt, extracellular signal regulated kinase (ERK), and protein kinase C (PKC) pathways (1-4). Dysregulation of the ErbB signaling pathway is a common alteration in human cancer, and it occurs largely as a consequence of gain-offunction mutations (e.g., EGFR); gene amplification (e.g., ErbB2); and/or overexpression of ErbB ligands, such as EGF and transforming growth factor alpha (TGF␣) (EGFR ligands) and heregulin-1/neuregulin-1 (HRG) (ErbB3/ErbB4 ligand) (5-10).ErbB3 has been shown to be crucially important in breast cancer progression. This receptor is catalytically inactive, and hence, its signaling capacity depends entirely on dimerization with other catalytically competent ErbB partners. ErbB2, the only orphan member of the ErbB receptor family, is the preferred dimerization partner for ErbB3, and the ErbB2/ErbB3 heterodimer, which signals preferentially through PI3K, is regarded as a major oncog...

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confidence: 99%

Heregulin/ErbB3 Signaling Enhances CXCR4-Driven Rac1 Activation and Breast Cancer Cell Motility via Hypoxia-Inducible Factor 1α

López‐Haber

Barrio-Real

Casado‐Medrano

et al. 2016

Molecular and Cellular Biology

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“…Induction of vimentin by HRG in this study was very weak and disappeared after 24 h (J. Kim et al, 2013). Besides, while in SKBr3 cells we observed strong induction of Snail after HRG treatment for 48 h, Kim et al did not see any difference between HRG-treated and the control group (J.…”

Section: 6) a Recent Study By Kim Et Al (Published After We Perfomentioning

confidence: 47%

“…Besides, this study showed induction of Snail, vimentin and fibronectin in response to HRG treatment (J. Kim et al, 2013). Induction of vimentin by HRG in this study was very weak and disappeared after 24 h (J.…”

Section: 6) a Recent Study By Kim Et Al (Published After We Perfomentioning

confidence: 53%

“…Besides, while in SKBr3 cells we observed strong induction of Snail after HRG treatment for 48 h, Kim et al did not see any difference between HRG-treated and the control group (J. Kim et al, 2013). The discrepancies between the two studies might be due to differences in the antibodies purchased from different companies.…”

Section: 6) a Recent Study By Kim Et Al (Published After We Perfomentioning

confidence: 57%

“…conditions and assay end-points for analysis of the effects of HRG on cancer cell lines (e.g. (Beji et al, 2012;Dagnell et al, 2013;J. Kim et al, 2013;P.…”

Section: Hrg Induces Mmp-9 Transcript In Mda361 Mcf7 and Skbr3 Cellsmentioning

confidence: 99%

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Heregulin (Neuregulin)/HER3 signalling increases invasive behaviour of HER2-positive breast cancer cells

Momeny¹

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Breast cancer is a heterogeneous disease with distinct histological and molecular subtypes differing in prognosis, response to therapy and metastatic behaviour. Like most cancers, poor outcome in breast cancer is related to tumour cell spread and colonisation of distant organs, which ultimately disrupts local and systemic physiological processes to the demise of the patient. Colonisation of the brain is arguably the most aggressive manifestation of metastatic disease. Brain metastasis is a growing public health problem associated with a high degree of morbidity and virtually 100% mortality. The current treatments for these patients are surgery, radiotherapy and chemotherapy, but their outcome remains poor. In this regard, the management of brain metastases is an unmet medical need for which establishment of more effective preventive and therapeutic treatment strategies is of paramount importance. In order to achieve that, we need to deepen our knowledge and insights about the molecular mechanisms and signal transduction pathways underlying initiation and progression of brain metastases.Invasion of breast tumour cells across the basement membrane and endothelium to gain entry to the blood stream and lymphovascular system is a critical early requirement for metastasis.Disseminated cells must then undergo extravasation at distant tissue sites. In the case of brain metastases, cells must breach the highly specialised and impermeable blood-brain-barrier.Improving our understanding of the molecular mechanisms underlying these processes may reveal new drug targets to prevent development or suppress growth of these lethal tumours.Of all the breast cancer subtypes, patients with HER2-positive disease (amplification and/or overexpression of the ERBB2 receptor tyrosine kinase) exhibit the highest frequency of brain metastases. Both HER2 and its obligate dimerisation partner, HER3 (ERBB3), are associated with development of brain metastases, though a mechanistic link has not yet been established.The main goal of this project was to elucidate the molecular mechanisms by which the HER2/HER3 heterodimer promotes metastatic progression and more specifically, development of brain metastases. In order to achieve this, activation of the HER2/HER3 iv

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Targeted Inhibition of Snail Activity in Breast Cancer Cells by Using a Co^III‐Ebox Conjugate

et al. 2015

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The transition from a non-invasive to an invasive phenotype is an essential step in tumor metastasis. The Snail family of transcription factors (TFs) is known to play a significant role in this transition. These TFs are zinc fingers that bind to the CAGGTG Ebox consensus sequence. CoIII-Ebox is a cobalt(III) complex attached to an Ebox oligonucleotide that confers specificity towards Snail TFs. CoIII-Ebox has been shown to inhibit Snail-mediated embryonic neural crest development in Xenopus laevis, but its efficacy in inhibiting Snail-induced cancer cell invasiveness has not been explored. Here, we describe the efficacy of CoIII-Ebox in inhibiting the invasive aspects of heregulin β1(HRG)-treated breast cancer cells. CoIII-Ebox was found to inhibit the capacity of Snail to repress target genes after HRG induction. Snail inhibition by CoIII-Ebox reduced the invasive propensity of cells in 2D and 3D, thereby demonstrating promise in inhibiting metastasis.

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HRG-β1-driven ErbB3 signaling induces epithelial–mesenchymal transition in breast cancer cells

Cited by 33 publications

References 34 publications

Heregulin/ErbB3 Signaling Enhances CXCR4-Driven Rac1 Activation and Breast Cancer Cell Motility via Hypoxia-Inducible Factor 1α

Heregulin/ErbB3 Signaling Enhances CXCR4-Driven Rac1 Activation and Breast Cancer Cell Motility via Hypoxia-Inducible Factor 1α

Heregulin (Neuregulin)/HER3 signalling increases invasive behaviour of HER2-positive breast cancer cells

Targeted Inhibition of Snail Activity in Breast Cancer Cells by Using a Co^III‐Ebox Conjugate

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HRG-β1-driven ErbB3 signaling induces epithelial–mesenchymal transition in breast cancer cells

Cited by 33 publications

References 34 publications

Heregulin/ErbB3 Signaling Enhances CXCR4-Driven Rac1 Activation and Breast Cancer Cell Motility via Hypoxia-Inducible Factor 1α

Heregulin/ErbB3 Signaling Enhances CXCR4-Driven Rac1 Activation and Breast Cancer Cell Motility via Hypoxia-Inducible Factor 1α

Heregulin (Neuregulin)/HER3 signalling increases invasive behaviour of HER2-positive breast cancer cells

Targeted Inhibition of Snail Activity in Breast Cancer Cells by Using a CoIII‐Ebox Conjugate

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Targeted Inhibition of Snail Activity in Breast Cancer Cells by Using a Co^III‐Ebox Conjugate