ErbB4/HER4: Role in Mammary Gland Development, Differentiation and Growth Inhibition

Muraoka-Cook, Rebecca S.; Feng, Shu Mang; Strunk, Karen E.; Earp, Shelton

doi:10.1007/s10911-008-9080-x

Cited by 91 publications

(95 citation statements)

References 81 publications

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“…ErbB2/HER2 overexpression due to HER2 gene amplification results in formation of HER2-related breast cancers (27). There is little consensus about the role of ErbB4 in models of breast cancer, perhaps due to the multitude of splice variations affecting its signaling capabilities and biological outcomes or due to its role in promoting secretory differentiation of the breast epithelium (34). Because ErbB3 is kinase impaired, its role in breast cancer has been framed by its ability to heterodimerize with HER2 and EGFR (26,35).…”

Section: Discussionmentioning

confidence: 99%

ErbB3 downregulation enhances luminal breast tumor response to antiestrogens

et al. 2013

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IntroductionAberrant regulation of the erythroblastosis oncogene B (ErbB) family of receptor tyrosine kinases (RTKs) and their ligands is common in human cancers (1-4). This family consists of 4 related members, HER1/ErbB1/EGFR, HER2/ErbB2/Neu, HER3/ ErbB3, and HER4/ErbB4. Except for ErbB3, which has very weak kinase activity, the ErbB RTKs exhibit dimerization-induced tyrosine phosphorylation and catalytic activation that results in signal transduction to intracellular targets. ErbBs are able to form homodimers as well as heterodimers with other coreceptors of the ErbB family. ErbB3 relies on transphosphorylation by heterodimeric partners to induce signal transduction (5-7). Therefore, therapeutic interest in the ErbB family has been historically focused on EGFR and ErbB2.HER2/ErbB2 is gene amplified in nearly 25% of all breast cancers. Targeting HER2/ErbB2 activity using the monoclonal antibody trastuzumab or the small molecule tyrosine kinase inhibitor (TKI) lapatinib decreases growth of HER2-amplified breast cancer cells, improving survival and outcome of patients with breast cancers.Recently, clinical results demonstrate that therapeutic resistance to HER2/ErbB2 inhibitors occurs in part due to feedback upregulation of ErbB3 signaling, increasing the activity and output through the PI3K/mTOR pathway. This observation may underlie the recently

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Section: Discussionmentioning

confidence: 99%

ErbB3 downregulation enhances luminal breast tumor response to antiestrogens

et al. 2013

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“…The upregulation of ErbB4 transcripts correlates with the tumorigenic potential of MCF-7 cells expressing different p14 mutants. ErbB4 is a member of the EGF receptor family that mediates cell proliferation and differentiation and mammary gland differentiation in response to EGF-like growth factors (45). In human breast cancer cells, nuclear localization of ErbB4 correlates with poor survival (46).…”

Section: Discussionmentioning

confidence: 99%

“…Deletion of the first half of the NLS (R 29 -R 34 ) moved almost all of the p14 out of the nucleolus, leaving the majority in the nucleus, with a significant amount of the mutant p14 remaining in the cytoplasm. Deletion of the entire NLS (R 29 -R 45 ) resulted in all of the p14 remaining in the cytoplasm. This confirms that the sequence previously identified as the NLS is responsible for localization of p14, not only to the nucleus but also to the nucleolus.…”

Section: Intracellular Localization Of Mutant P14smentioning

confidence: 99%

The Signal Peptide of Mouse Mammary Tumor Virus-Env: A Phosphoprotein Tumor Modulator

Feldman

Roniger

Bar-Sinai

et al. 2012

Molecular Cancer Research

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Mouse mammary tumor virus (MMTV) is associated primarily with mammary carcinomas and lymphomas. The signal peptide of the MMTV envelope precursor is uniquely targeted to nucleoli of cells that harbor the virus, where it can function as a nuclear export factor for intron-containing transcripts. Antibodies to this signal peptide, which we refer to as p14, were previously shown to label nucleoli in a subset of human breast cancers. To look for additional cellular functions of p14, different mutants were ectopically expressed in the MCF-7 human breast cancer cell line. This approach identified motifs responsible for its nucleolar targeting, nucleocytoplasmic shuttling, target protein (B23, nucleophosmin) binding, and phosphorylation at serine 18 and 65 both in situ and in vitro. To test the role of these phosphorylation sites, we carried out in vivo tumorigenesis studies in severe combined immunodeficient mice. The findings show that the p14-Ser65Ala mutation is associated with impaired tumorigenicity, whereas the p14-Ser18Ala mutation is associated with enhanced tumorigenicity. Microarray analysis suggests that phosphorylation at serine 18 or at serine 65 is associated with transcriptional regulation of the L5 nucleolar ribosomal protein (a p14 target) and the Erb-B signal transduction pathway. Taken together, these results show that the phosphorylation status of p14 determines whether it functions as a pro-oncogenic or antioncogenic modulator.

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“…HER4/ERBB4 is a member of the EGFR family of receptor tyrosine kinases and is known to have both tumor suppressive and pro-oncogenic activity (67). Some of the tumorsuppressive functions of HER4/ERBB4 include growth inhibition and induced differentiation (68). Elevated levels of HER4/ERBB4 expression are associated with favorable outcomes in breast cancer and decreased recurrence rates of ductal carcinoma in situ, the precursor lesion to breast cancer (67,69,70).…”

Section: Proteomic Analysis Of Trastuzumab-resistant Breast Cancermentioning

confidence: 99%

Quantitative Proteomics with siRNA Screening Identifies Novel Mechanisms of Trastuzumab Resistance in HER2 Amplified Breast Cancers

Boyer

Collier

Vidavsky

et al. 2013

Molecular & Cellular Proteomics

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HER2 is a receptor tyrosine kinase that is overexpressed in 20% to 30% of human breast cancers and which affects patient prognosis and survival. Treatment of HER2-positive breast cancer with the monoclonal antibody trastuzumab (Herceptin) has improved patient survival, but the development of trastuzumab resistance is a major medical problem. Many of the known mechanisms of trastuzumab resistance cause changes in protein phosphorylation patterns, and therefore quantitative proteomics was used to examine phosphotyrosine signaling networks in trastuzumab-resistant cells. The model system used in this study was two pairs of trastuzumab-sensitive and -resistant breast cancer cell lines. Using stable isotope labeling, phosphotyrosine immunoprecipitations, and online TiO 2 chromatography utilizing a dual trap configuration, ϳ1700 proteins were quantified. Comparing quantified proteins between the two cell line pairs showed only a small number of common protein ratio changes, demonstrating heterogeneity in phosphotyrosine signaling networks across different trastuzumab-resistant cancers. Proteins showing significant increases in resistant versus sensitive cells were subjected to a focused siRNA screen to evaluate their functional relevance to trastuzumab resistance. The screen revealed proteins related to the Src kinase pathway, such as CDCP1/Trask, embryonal Fyn substrate, and Paxillin. We also identify several novel proteins that increased trastuzumab sensitivity in resistant cells when targeted by siRNAs, including FAM83A and MAPK1. These proteins may present targets for the development of clinical diagnostics or therapeutic strategies to guide the treatment of HER2؉ breast cancer patients who develop trastuzumab resistance. Molecular & Cellular Proteomics

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ErbB4/HER4: Role in Mammary Gland Development, Differentiation and Growth Inhibition

Cited by 91 publications

References 81 publications

ErbB3 downregulation enhances luminal breast tumor response to antiestrogens

ErbB3 downregulation enhances luminal breast tumor response to antiestrogens

The Signal Peptide of Mouse Mammary Tumor Virus-Env: A Phosphoprotein Tumor Modulator

Quantitative Proteomics with siRNA Screening Identifies Novel Mechanisms of Trastuzumab Resistance in HER2 Amplified Breast Cancers

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