An Activated ErbB3/NRG1 Autocrine Loop Supports In Vivo Proliferation in Ovarian Cancer Cells

Sheng, Qing; Liu, Xinggang; Fleming, Eleanor; Yuan, Karen; Piao, Huiying; Chen, Jinyun; Moustafa, Zeinab; Thomas, Roman K.; Greulich, Heidi; Schinzel, Anna C.; Zaghlul, Sara; Batt, David; Ettenberg, Seth A.; Meyerson, Matthew; Schoeberl, Birgit; Kung, Andrew L.; Hahn, William C.; Drapkin, Ronny; Livingston, David M.; Liu, Joyce F.

doi:10.1016/j.ccr.2009.12.047

Cited by 209 publications

(144 citation statements)

References 42 publications

Supporting

Mentioning

142

Contrasting

Order By: Relevance

“…Increasing evidence links HRG/ErbB3 signaling to mammary tumorigenesis and metastasis. In addition, studies have assigned key roles to autocrine HRG-mediated activation of ErbB3/ErbB2 in sustaining tumor growth and conferring resistance to therapeutic agents (15,17,25,26,28,(72)(73)(74). The fact that ErbB3 signals primarily through activation of the PI3K pathway (1,7,8) invariably argues for a prominent role of the receptor in shifting the balance toward enhanced cell survival, invasiveness, and the maintenance of the tumor phenotype.…”

Section: Discussionmentioning

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

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionmentioning

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

View full text Add to dashboard Cite

show abstract

“…However, many recent studies showed that this receptor is very important in cancer. ErbB3 has been regarded to cause cell proliferation of cancer cells (Sheng et al 2010), and some ErbB3-targeting drugs are being developed in their clinical phases, such as the ErbB3 antibody MM-121 . Therefore, miR-22 will be a potential therapeutic drug to target ErbB3 for treatment of lung cancer.…”

Section: Discussionmentioning

confidence: 99%

Tumor suppressor miR-22 suppresses lung cancer cell progression through post-transcriptional regulation of ErbB3

Ling

Wang

Long

et al. 2012

J Cancer Res Clin Oncol

View full text Add to dashboard Cite

show abstract

“…So far, no predominant pathway ('addicting' oncogene) has been shown in ovarian tumors. Although potentially promising, such an oncogene was recently described by Sheng et al 7 Several drug modalities have been developed to target ErbB3; however, the utility of these modalities remains to be clinically established.…”

Section: Introductionmentioning

confidence: 99%

BRCA1-IRIS inactivation sensitizes ovarian tumors to cisplatin

et al. 2014

View full text Add to dashboard Cite

Ovarian cancer is the first in mortalities among gynecologic cancers in the United States, often due to late diagnosis and/or acquired platinum-resistant recurrences. This study investigates whether BRCA1-IRIS is a novel treatment target for ovarian cancers and in platinum-resistant recurrences. Here we show that more than half of the ovarian cancer samples analyzed showed BRCA1-IRIS and survivin overexpression and lacked nuclear FOXO3a expression. Normal ovarian epithelial cells overexpressing BRCA1-IRIS formed metastasis in mice when injected in the peritoneal cavity, whereas aggressive ovarian cancer cell lines failed to form tumors or metastases in mice when BRCA1-IRIS was silenced in them. We show that BRCA1-IRIS activates two autocrine signaling loops, brain-derived neurotrophic factor/tyrosine kinase B receptor (BDNF/TrkB) and neuregulin 1 (NRG1)/ErbB2. These loops are involved in anoikis resistance and metastasis promotion. These loops operate in several ovarian cancer cell lines, and BRCA1-IRIS silencing or inactivation using a novel inhibitory peptide renders both non-functional and promoted cell death. In a mouse xenograft model, BRCA1-IRIS inactivation using this novel inhibitory peptide resulted in significant reduction in ovarian tumor growth. More importantly, this treatment sensitized ovarian tumors to low cisplatin concentrations. Taken together, these data strongly suggest that BRCA1-IRIS and/or BDNF/TrkB and NRG1/ErbB2 could serve as rational therapeutic targets for advanced ovarian cancers.

show abstract

An Activated ErbB3/NRG1 Autocrine Loop Supports In Vivo Proliferation in Ovarian Cancer Cells

Cited by 209 publications

References 42 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

Tumor suppressor miR-22 suppresses lung cancer cell progression through post-transcriptional regulation of ErbB3

BRCA1-IRIS inactivation sensitizes ovarian tumors to cisplatin

Contact Info

Product

Resources

About