Loss of Nrdp1 enhances ErbB2/ErbB3-dependent breast tumor cell growth.

Dysregulation of ErbB receptor tyrosine kinases is thought to promote mammary tumor progression by stimulating tumor cell growth and invasion. Overexpression and aberrant activation of ErbB2/HER2 confer aggressive and malignant characteristics to breast cancer cells, and patients displaying ErbB2-amplified breast cancer face a worsened prognosis. Recent studies have established that ErbB2 and ErbB3 are commonly co-overexpressed in breast tumor cell lines and in patient samples. ErbB2 heterodimerizes with and activates the ErbB3 receptor, and the two receptors synergize in promoting growth factor-induced cell proliferation, transformation, and invasiveness. Our previous studies have shown that the neuregulin receptor degradation protein-1 (Nrdp1) E3 ubiquitin ligase specifically suppresses cellular ErbB3 levels by marking the receptor for proteolytic degradation. Here, we show that overexpression of Nrdp1 in human breast cancer cells results in the suppression of ErbB3 levels, accompanied by the inhibition of cell growth and motility and the attenuation of signal transduction pathways. In contrast, either Nrdp1 knockdown or the overexpression of a dominant-negative form enhances ErbB3 levels and cellular proliferation. Additionally, Nrdp1 expression levels inversely correlate with ErbB3 levels in primary human breast cancer tissue and in a mouse model of ErbB2 mammary tumorigenesis. Our observations suggest that Nrdp1-mediated ErbB3 degradation suppresses cellular growth and motility, and that Nrdp1 loss in breast tumors may promote tumor progression by augmenting ErbB2/ErbB3 signaling.

[1]  J. Segall,et al.  ErbB3-dependent motility and intravasation in breast cancer metastasis. , 2006, Cancer research.

[2]  Roger L. Williams,et al.  Phosphoinositide 3-kinases as drug targets in cancer. , 2005, Current opinion in pharmacology.

[3]  A. Thor,et al.  Functional interaction between mouse erbB3 and wild-type rat c-neu in transgenic mouse mammary tumor cells , 2005, Breast Cancer Research.

[4]  S. Wiseman,et al.  Coexpression of the type 1 growth factor receptor family members HER‐1, HER‐2, and HER‐3 has a synergistic negative prognostic effect on breast carcinoma survival , 2005, Cancer.

[5]  Ken Jacobson,et al.  MAP kinases and cell migration , 2004, Journal of Cell Science.

[6]  A. Goldberg,et al.  Nrdp1‐mediated degradation of the gigantic IAP, BRUCE, is a novel pathway for triggering apoptosis , 2004, The EMBO journal.

[7]  K. Carraway,et al.  Negative regulation of ErbB family receptor tyrosine kinases , 2004, British Journal of Cancer.

[8]  I. Bièche,et al.  Prognostic value of ERBB family mRNA expression in breast carcinomas , 2003, International journal of cancer.

[9]  F. Maurer,et al.  The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[10]  J. R. Reeves,et al.  Expression of the HER1–4 family of receptor tyrosine kinases in breast cancer , 2003, The Journal of pathology.

[11]  J. Koland,et al.  Roles of mitogen-activated protein kinase and phosphoinositide 3'-kinase in ErbB2/ErbB3 coreceptor-mediated heregulin signaling. , 2003, Experimental cell research.

[12]  A. Citri,et al.  The deaf and the dumb: the biology of ErbB-2 and ErbB-3. , 2003, Experimental cell research.

[13]  H. Esumi,et al.  Differential regulation of tumor angiogenesis by distinct ErbB homo- and heterodimers. , 2002, Molecular biology of the cell.

[14]  A. Goldberg,et al.  Nrdp1/FLRF is a ubiquitin ligase promoting ubiquitination and degradation of the epidermal growth factor receptor family member, ErbB3 , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[15]  R. Neve,et al.  Distinct roles for phosphoinositide 3-kinase, mitogen-activated protein kinase and p38 MAPK in mediating cell cycle progression of breast cancer cells , 2002, Oncogene.

[16]  K. M. Nicholson,et al.  The protein kinase B/Akt signalling pathway in human malignancy. , 2002, Cellular signalling.

[17]  K. Carraway,et al.  An RBCC protein implicated in maintenance of steady-state neuregulin receptor levels , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[18]  R. Tibshirani,et al.  Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[19]  M. Cobb,et al.  Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. , 2001, Endocrine reviews.

[20]  M. Karin,et al.  Mammalian MAP kinase signalling cascades , 2001, Nature.

[21]  Y. Yarden,et al.  Untangling the ErbB signalling network , 2001, Nature Reviews Molecular Cell Biology.

[22]  Y. Chiew,et al.  Expression of c‐erbB receptors, heregulin and oestrogen receptor in human breast cell lines , 2000, International journal of cancer.

[23]  Jie Leng,et al.  ErbB2 Is Necessary for Induction of Carcinoma Cell Invasion by Erbb Family Receptor Tyrosine Kinases , 2000, The Journal of cell biology.

[24]  R. Lupu,et al.  Heregulin regulates the actin cytoskeleton and promotes invasive properties in breast cancer cell lines. , 1999, International journal of oncology.

[25]  Y. Shimizu,et al.  Stimulation of beta1-integrin function by epidermal growth factor and heregulin-beta has distinct requirements for erbB2 but a similar dependence on phosphoinositide 3-OH kinase. , 1999, Molecular biology of the cell.

[26]  R. Cardiff,et al.  Elevated expression of activated forms of Neu/ErbB‐2 and ErbB‐3 are involved in the induction of mammary tumors in transgenic mice: implications for human breast cancer , 1999, The EMBO journal.

[27]  L. Cantley,et al.  New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[28]  Dihua Yu,et al.  Heregulin β1-activated Phosphatidylinositol 3-Kinase Enhances Aggregation of MCF-7 Breast Cancer Cells Independent of Extracellular Signal-regulated Kinase , 1999 .

[29]  Kuala Lumpur Malaysia,et al.  Expression of c-erbB3 protein in primary breast carcinomas. , 1998, British Journal of Cancer.

[30]  P. W. Janes,et al.  Inhibition of the MAP kinase cascade blocks heregulin-induced cell cycle progression in T-47D human breast cancer cells , 1998, Oncogene.

[31]  D. Stern,et al.  Specificity within the EGF family/ErbB receptor family signaling network , 1998, BioEssays : news and reviews in molecular, cellular and developmental biology.

[32]  R. Whitaker,et al.  Heregulin and agonistic anti-p185(c-erbB2) antibodies inhibit proliferation but increase invasiveness of breast cancer cells that overexpress p185(c-erbB2): increased invasiveness may contribute to poor prognosis. , 1997, Clinical cancer research : an official journal of the American Association for Cancer Research.

[33]  Y. Yarden,et al.  The ErbB signaling network in embryogenesis and oncogenesis: signal diversification through combinatorial ligand‐receptor interactions , 1997, FEBS letters.

[34]  R. Mulligan,et al.  A stable human-derived packaging cell line for production of high titer retrovirus/vesicular stomatitis virus G pseudotypes. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[35]  Y. Yarden,et al.  Diversification of Neu differentiation factor and epidermal growth factor signaling by combinatorial receptor interactions. , 1996, The EMBO journal.

[36]  A. Ullrich,et al.  Heregulin‐dependent regulation of HER2/neu oncogenic signaling by heterodimerization with HER3. , 1995, The EMBO journal.

[37]  H. Earp,et al.  Heterodimerization and functional interaction between EGF receptor family members: a new signaling paradigm with implications for breast cancer research , 1995, Breast Cancer Research and Treatment.

[38]  N. Normanno,et al.  Epidermal growth factor-related peptides and their receptors in human malignancies. , 1995, Critical reviews in oncology/hematology.

[39]  M. Kraus,et al.  Cooperative signaling of ErbB3 and ErbB2 in neoplastic transformation and human mammary carcinomas. , 1995, Oncogene.

[40]  N. Hynes,et al.  The biology of erbB-2/neu/HER-2 and its role in cancer. , 1994, Biochimica et biophysica acta.

[41]  L. Cantley,et al.  Insect cell-expressed p180erbB3 possesses an impaired tyrosine kinase activity. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[42]  L. Cantley,et al.  A neu acquaintance for ErbB3 and ErbB4: A role for receptor heterodimerization in growth signaling , 1994, Cell.

[43]  Y. Yarden,et al.  A single autophosphorylation site confers oncogenicity to the Neu/ErbB‐2 receptor and enables coupling to the MAP kinase pathway. , 1994, The EMBO journal.

[44]  R Akita,et al.  Her-2/neu expression in node-negative breast cancer: direct tissue quantitation by computerized image analysis and association of overexpression with increased risk of recurrent disease. , 1993, Cancer research.

[45]  D. Barnes,et al.  Expression of the ERBB3 gene product in breast cancer. , 1992, British Journal of Cancer.

[46]  K. Kuroi,et al.  Prognostic significance of co-expression of c-erbB-2 oncoprotein and epidermal growth factor receptor in breast cancer patients. , 1992, American journal of surgery.

[47]  Y. Yarden,et al.  Regulated coupling of the Neu receptor to phosphatidylinositol 3'-kinase and its release by oncogenic activation. , 1992, The Journal of biological chemistry.

[48]  T. Barrette,et al.  ONCOMINE: a cancer microarray database and integrated data-mining platform. , 2004, Neoplasia.

[49]  John F. Timms,et al.  Cellular function of phosphoinositide 3-kinases: Implications for development, immunity, homeostasis, and cancer , 2001 .

[50]  W. McGuire,et al.  Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. , 1987, Science.