Growth regulation of human breast and ovarian tumor cells by heregulin: Evidence for the requirement of ErbB2 as a critical component in mediating heregulin responsiveness.

Alterations in the expression of the epidermal growth factor (EGF) receptor ErbB family are frequently encountered in a number of human cancers. Two of these receptors, ErbB3 and ErbB4, are known to bind a family of related proteins termed heregulins (HRGs) or neu differentiation factors. In biologically relevant systems, interaction of HRG with ErbB3 or ErbB4 results in the transactivation of ErbB2. In this report, we show that ErbB2 is a critical component in mediating HRG responsiveness in a panel of human breast and ovarian tumor cell lines. Because HRGs have been reported to elicit diverse biological effects on cultured cells, including growth stimulation, growth inhibition, and induction of differentiation, we systematically examined the effect of rHRG beta 1 on tumor cell proliferation. HRG binding studies were performed with a panel of breast and ovarian tumor cell lines expressing a range of levels of ErbB2. The biological responses to HRG were also compared to EGF and to the growth-inhibitory anti-ErbB2 antibody, 4D5. In most cases, HRG stimulation of DNA synthesis correlated with positive effects on cell cycle progression and cell number and with enhancement of colony formation in soft agar. On each cell line tested, the HRG effects were distinguishable from EGF and 4D5. Our findings indicate that HRG induces cell proliferation in a number of tumor cell lines. In addition, we show that methods for measuring cell proliferation, as well as experimental conditions, are critical for determining HRGs effect on tumor cell growth in vitro.

[1]  Y. Yarden,et al.  Neu differentiation factor activation of ErbB-3 and ErbB-4 is cell specific and displays a differential requirement for ErbB-2 , 1995, Molecular and cellular biology.

[2]  Rüdiger Klein,et al.  Aberrant neural and cardiac development in mice lacking the ErbB4 neuregulin receptor , 1995, Nature.

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

[4]  M. Sliwkowski,et al.  HER-2 tyrosine kinase pathway targets estrogen receptor and promotes hormone-independent growth in human breast cancer cells. , 1995, Oncogene.

[5]  S. Ethier,et al.  Mitogenic activity of neu differentiation factor/heregulin mimics that of epidermal growth factor and insulin‐like growth factor‐I in human mammary epithelial cells , 1995, Journal of cellular physiology.

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

[7]  C. Cordon-Cardo,et al.  Changing pattern of expression of the epidermal growth factor receptor and transforming growth factor alpha in the progression of prostatic neoplasms. , 1995, Clinical cancer research : an official journal of the American Association for Cancer Research.

[8]  L. Cantley,et al.  Heregulin Stimulates Mitogenesis and Phosphatidylinositol 3-Kinase in Mouse Fibroblasts Transfected with erbB2/neu and erbB3(*) , 1995, The Journal of Biological Chemistry.

[9]  B. Groner,et al.  Targeted inhibition of tumor‐cell growth by recombinant heregulin‐toxin fusion proteins , 1995, International journal of cancer.

[10]  N. Hynes,et al.  Single-chain antibody-mediated intracellular retention of ErbB-2 impairs Neu differentiation factor and epidermal growth factor signaling , 1995, Molecular and cellular biology.

[11]  M. Sliwkowski,et al.  The influence of heregulins on human Schwann cell proliferation , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[12]  D. Taverna,et al.  NDF/heregulin activates MAP kinase and p70/p85 S6 kinase during proliferation or differentiation of mammary epithelial cells. , 1995, Oncogene.

[13]  D. Taverna,et al.  Neu differentiation factor/heregulin modulates growth and differentiation of HC11 mammary epithelial cells. , 1995, Molecular endocrinology.

[14]  C. Bucana,et al.  Level and function of epidermal growth factor receptor predict the metastatic potential of human colon carcinoma cells. , 1995, Clinical cancer research : an official journal of the American Association for Cancer Research.

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

[16]  E. Peles,et al.  ErbB-3 and ErbB-4 function as the respective low and high affinity receptors of all Neu differentiation factor/heregulin isoforms. , 1994, The Journal of biological chemistry.

[17]  H. Kim,et al.  Epidermal growth factor-dependent association of phosphatidylinositol 3-kinase with the erbB3 gene product. , 1994, The Journal of biological chemistry.

[18]  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.

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

[20]  M. White,et al.  The IRS-1 signaling system. , 1994, Trends in biochemical sciences.

[21]  L. Cantley,et al.  ErbB3 is involved in activation of phosphatidylinositol 3-kinase by epidermal growth factor , 1994, Molecular and cellular biology.

[22]  M. Sliwkowski,et al.  Coexpression of erbB2 and erbB3 proteins reconstitutes a high affinity receptor for heregulin. , 1994, The Journal of biological chemistry.

[23]  L. Cantley,et al.  The erbB3 gene product is a receptor for heregulin. , 1994, The Journal of biological chemistry.

[24]  M. White.  The IRS-1 signaling system. , 1994, Current opinion in genetics & development.

[25]  H. Modjtahedi,et al.  The receptor for EGF and its ligands - expression, prognostic value and target for therapy in cancer (review). , 1994, International journal of oncology.

[26]  J. Baselga,et al.  Receptor blockade with monoclomal antibodies as anti-cancer therapy , 1994 .

[27]  J. Baselga,et al.  Receptor blockade with monoclonal antibodies as anti-cancer therapy. , 1994, Pharmacology & therapeutics.

[28]  G. Plowman,et al.  Heregulin induces tyrosine phosphorylation of HER4/p180erbB4 , 1993, Nature.

[29]  R. Lupu,et al.  Neu differentiation factor (heregulin) induces expression of intercellular adhesion molecule 1: implications for mammary tumors. , 1993, Cancer research.

[30]  W. Wood,et al.  Assignment of heregulin (HGL) to human chromosome 8p22-p11 by PCR analysis of somatic cell hybrid DNA. , 1993, Genomics.

[31]  M. Kraus,et al.  Demonstration of ligand-dependent signaling by the erbB-3 tyrosine kinase and its constitutive activation in human breast tumor cells. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[32]  G. Scott,et al.  A truncated intracellular HER2/neu receptor produced by alternative RNA processing affects growth of human carcinoma cells , 1993, Molecular and cellular biology.

[33]  William Arbuthnot Sir Lane,et al.  ARIA, a protein that stimulates acetylcholine receptor synthesis, is a member of the neu ligand family , 1993, Cell.

[34]  Y. Yarden,et al.  Neural expression and chromosomal mapping of Neu differentiation factor to 8p12-p21. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[35]  G. Plowman,et al.  Ligand-specific activation of HER4/p180erbB4, a fourth member of the epidermal growth factor receptor family. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[36]  H. Ne.  Amplification and overexpression of the erbB-2 gene in human tumors: its involvement in tumor development, significance as a prognostic factor, and potential as a target for cancer therapy. , 1993, Seminars in cancer biology.

[37]  N. Hynes,et al.  Amplification and overexpression of the erbB-2 gene in human tumors: its involvement in tumor development, significance as a prognostic factor, and potential as a target for cancer therapy. , 1993, Seminars in cancer biology.

[38]  D. Slamon,et al.  Transformation mediated by the human HER-2 gene independent of the epidermal growth factor receptor. , 1992, Oncogene.

[39]  R. Lupu,et al.  A ligand for the erbB-2 oncogene product (gp30) induces differentiation of human breast cancer cells. , 1992, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[40]  R. Koski,et al.  Neu differentiation factor: A transmembrane glycoprotein containing an EGF domain and an immunoglobulin homology unit , 1992, Cell.

[41]  Yosef Yarden,et al.  Isolation of the Neu HER-2 stimulatory ligand: A 44 kd glycoprotein that induces differentiation of mammary tumor cells , 1992, Cell.

[42]  N. Lemoine,et al.  The type 1 (EGFR-related) family of growth factor receptors and their ligands. , 1992, Progress in growth factor research.

[43]  R. Lupu,et al.  Direct interaction of a ligand for the erbB2 oncogene product with the EGF receptor and p185erbB2. , 1990, Science.

[44]  B. Katzenellenbogen,et al.  Hormonal modulation of HER-2/neu protooncogene messenger ribonucleic acid and p185 protein expression in human breast cancer cell lines. , 1990, Cancer research.

[45]  A. Ullrich,et al.  Characterization of murine monoclonal antibodies reactive to either the human epidermal growth factor receptor or HER2/neu gene product. , 1990, Cancer research.

[46]  A. Ullrich,et al.  p185HER2 monoclonal antibody has antiproliferative effects in vitro and sensitizes human breast tumor cells to tumor necrosis factor , 1989, Molecular and cellular biology.

[47]  N. Shimizu,et al.  Stimulation by EGF of the growth of EGF receptor‐hyperproducing tumor cells in athymic mice , 1987, International journal of cancer.

[48]  E. Gelmann,et al.  Epidermal growth factor receptor gene expression in estrogen receptor-positive and negative human breast cancer cell lines. , 1987, Molecular endocrinology.

[49]  M. Kraus,et al.  Overexpression of the EGF receptor‐related proto‐oncogene erbB‐2 in human mammary tumor cell lines by different molecular mechanisms. , 1987, The EMBO journal.

[50]  S. Jozan,et al.  Oestradiol is effective in stimulating 3H‐Thymidine Incorporation But Not On Proliferation of Breast Cancer Cultured Cells , 1985, Cell and tissue kinetics.

[51]  M N Pollak,et al.  MDA-468, a human breast cancer cell line with a high number of epidermal growth factor (EGF) receptors, has an amplified EGF receptor gene and is growth inhibited by EGF. , 1985, Biochemical and biophysical research communications.

[52]  D. Barnes.  Epidermal growth factor inhibits growth of A431 human epidermoid carcinoma in serum-free cell culture , 1982, The Journal of cell biology.

[53]  G. Gill,et al.  Increased phosphotyrosine content and inhibition of proliferation in EGF-treated A431 cells , 1981, Nature.

[54]  M. Karasek,et al.  LIMITATIONS IN THE USE OF [3H]THYMIDINE INCORPORATION INTO DNA AS AN INDICATOR OF EPIDERMAL KERATINOCYTE PROLIFERATION IN VITRO , 1979, Cell and tissue kinetics.