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Breast Cancer Research and Treatment

, Volume 31, Issue 2–3, pp 175–182 | Cite as

Modulation of breast cancer progression and differentiation by thegp30/neregulin

  • A. Staebler
  • C. Sommers
  • S. C. Mueller
  • S. Byers
  • E. W. Thompson
  • R. Lupu
Article

Summary

In the last decade we have come to understand that the growth of cancer cells in general and of breast cancer in particular depends, in many cases, upon growth factors that will bind to and activate their receptors. One of these growth factor receptors is theerbB-2 protein which plays an important role in the prognosis of breast cancer and is overexpressed in nearly 30% of human breast cancer patients. While evidence accumulates to support the relationship betweenerbB-2 overexpression and poor overall survival in breast cancer, understanding of the biological consequence(s) oferbB-2 overexpression remains elusive. Our recent discovery of thegp30 has allowed us to identify a number of related but distinct biological endpoints which appear responsive to signal transduction through theerbB-2 receptor. These endpoints of growth, invasiveness, and differentiation have clear implications for the emergence, maintenance and/or control of malignancy, and represent established endpoints in the assessment of malignant progression in breast cancer. We have shown thatgp30 induces a biphasic growth effect on cells witherbB-2 over-expression. We have recently determined the protein sequence ofgp30 and cloned its full length cDNA sequence. We have also cloned two additional forms to the ligand, that are believed to be different isoforms. We are currently expressing the different forms in order to determine their biological effects. To elucidate the cellular mechanisms underlying cell growth inhibition bygp30, we tested the effect of this ligand on cell growth and differentiation of the human breast cancer cells which overexpresserbB-2 and cells which express low levels of this protooncogene. High concentrations of ligand induced differentiation of cells overexpressingerbB-2, as measured by inhibition of cell growth, and increased synthesis of milk components, and modulation of E-cadherin and up-regulation of c-jun and c-fos. These findings indicate that ligand-induced growth inhibition in cells overexpressingerbB-2 is associated with an apparent induction of differentiation. The availability ofgp30 derived synthetic peptides and its full cDNAs provides tools necessary to acquire a better understanding of the mechanism of action of the this ligands and theerbB-2 receptor in breast cancer.

Keywords

Breast Cancer Breast Cancer Cell Breast Cancer Patient Human Breast Cancer Full Length cDNA 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J, Ullrich A, Press MF: Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244: 707–712, 1988Google Scholar
  2. 2.
    Paik SM, Hazan R, Fischer ER, Sass RE, Fischer B, Redmond C, Schlessinger Y, Lippman ME, King CR: Pathological findings from National Surgical Adjuvant Breast Project (protocol B-06), Prognostic significance oferbB-2 protein overexpression in primary breast cancer. J Clin Onc 1989Google Scholar
  3. 3.
    Wright C, Angus B, Nicholson S, Sainsbury JR, Cairns J, Gullick WJ, Kelly P, Harris AL, Horne CH: Expression oferbB-2 oncoprotein: a prognostic indicator in human breast cancer. Cancer Res 49: 2087–2090, 1989Google Scholar
  4. 4.
    Schechter AL, Stern DF, Vaidyanathan L, Decker SJ: The neu oncogene: and erbB-related gene encoding a 185,000 Mr tumor antigen. Nature 312: 513–516, 1984Google Scholar
  5. 5.
    Di Fiore PP, Pierce JH, Kraus MH, Segatto O, King CR, Aaronson SA:erbB-2 is a potent oncogene, when overexpressed in NIH/3T3 cells. Science 237: 178–182, 1986Google Scholar
  6. 6.
    Hudziak RM, Schlessinger J, Ullrich A: Increased expression of the putative growth factor receptor p185 (HER2) causes transformation and tumorigenesis of NIH/3T3 cells. PNAS 84: 177–182, 1987Google Scholar
  7. 7.
    Yamamoto T, Ikawa S, Akiyama T, Semba K, Nomura N, Miyajima N, Saito T, Toyoshima K: Similarity of protein encoded by the humanerbB-2 gene to epidermal growth factor receptor. Nature 319: 230–234, 1986Google Scholar
  8. 8.
    Schechter AL, Stern DF, Vaidyanathan L: An erbB related gene encoding a 185,000-Mw tumor antigen. Nature 312: 513–516, 1984Google Scholar
  9. 9.
    Semba K, Kamata N, Toyoshima K, Yamamoto T: An erbB related protooncogene,erbB-2, is distinct from theerbB-1/epidermal growth factor receptor gene and is amplified in a human salivary gland adenocarcinoma. PNAS USA 82: 6497–6501, 1985Google Scholar
  10. 10.
    Bargmann CI, Hung MC, Weinberg RA: The neu oncogene encodes an epidermal growth factor receptor related protein. Nature 319: 226–230, 1986Google Scholar
  11. 11.
    Coussens L, Yang-Feng TL, Liao YC, Chen E, Gray A, McGrath J, Seeberg PhH, Libermann TA, Schlessinger J, Franke U, Levinson A, Ullrich A: Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with the neu oncogene. Science 230: 1130–1139, 1985Google Scholar
  12. 12.
    Fukushige SI, Matsubaru K, Yoshida M: Localization of a novel v-erbB-related gene,erbB-2 on chromosome 17 and its amplification in a gastric cell line. Mol Cell biol 6: 955–958, 1986Google Scholar
  13. 13.
    Di Marco E, Pierce JH, Knicley CL, Di Fiore PP: Transformation of NIH 3T3 cells by overexpression of the normal coding sequence of the rat neu gene. Mol Cell biol 10: 3247–3252, 1990Google Scholar
  14. 14.
    Guy CT, Webster MA, Schaller M, Parsons TJ, Cardiff RD, Muller WJ: Expression of the neu protooncogene in the mammary epithelium of transgenic mice induces metastatic disease. Proc Natl Acad Sci USA 89: 10578–10582, 1992Google Scholar
  15. 15.
    Lupu R, Colomer R, Zugmaier G, Shepard M, Slamon D, Lippman ME: Direct interaction of a ligand for theerbB-2 oncogene product with the EGF receptor and p185erbB2. Science 249: 1552–1555, 1990Google Scholar
  16. 16.
    Lupu R, Wellstein A, Sheridan J, Ennis BW, Zugmaier G, Katz D, Lippman D, Dickson RB: Purification and characterization of a novel growth factor from human breast cancer cells. Biochem 1992Google Scholar
  17. 17.
    Lupu R, Colomer R, Kannan B, Lippman ME: A novel growth factor binds exclusively to theerbB-2 receptor and induces cellular responses. Proc Natl Acad Sci, USA, 1992Google Scholar
  18. 18.
    Lupu R, Perez C, Neri C, Cho C, Lippman ME: Cloning of a family of ligands for theerbB-2 receptor. Submitted to Science (1993)Google Scholar
  19. 19.
    Holmes W, Lewis G, Shepard MH, Kuang WJ, Wood WI, Goeddel DV, Vandlen RL: Identification of Heregulin, a specific activator of p185erbB2. Science, Vol 256, 1205–1210 (1992)Google Scholar
  20. 20.
    Falls DL, Rosen KM, Corfas G, Lane WS, Fischbach GD: ARIA, a protein that stimulates acetylcholine receptor synthesis is a member of the neu ligand family. Cell 72: 801–815, 1993Google Scholar
  21. 21.
    Peles E, Bacus SS, Koski RA, Lu HS, Wen D, Ogden SG, BenLevy R, Yarden Y: Isolation of the neu/HER-2 stimulatory ligand: a 44 kd glycoprotein that induces differentiation of mammary tumor cells. Cell 69: 205–216, 1992Google Scholar
  22. 22.
    Tarahovsky A, Zaichuk T, Prassolov V, Butenko ZA: A 25-kDa polypeptide is the ligand for p185neu and is secreted by activated macrophages. Oncogene 6: 2187–2196, 1991Google Scholar
  23. 23.
    Huang SS, Huang JS: Purification and characterization of the neu/erbB-2 ligand growth factor from bovine kidney. J Biol Chem 267: 11508–11612, 1992Google Scholar
  24. 24.
    Van de Vijver MJ, Peterse JL, Mooi WJ, Wisman P, Lomans L, Delesio O, Nusse R: Neu protein expression in breast cancer. Association with comedotype ductal carcinomain situ and limited prognostic value in stage II breast cancer. N Engl J Med 319: 1235–1245, 1988Google Scholar
  25. 25.
    Bartkova J, Barnes DM, Millis RR, Gullik WJ: Immunohistochemical demonstration oferbB-2 protein in mammary ductal carcinomain situ. Hum Pathol 21: 1164–1167, 1990Google Scholar
  26. 26.
    Muller W, Sinn E, Patengale P, Wallace R, Leder P: Single step induction of mammary adenocarcinoma in transgenic mice carrying the MMTV/c-neu oncogene. Cell 57: 931–936, 1989Google Scholar
  27. 27.
    Guy CT, Webster MA, Schaller M, Parsons TJ, Cardiff RD, Muller WJ: Expression of the neu protooncogene in the mammary epithelium of transgenic mice induces metastatic disease. Proc Natl Acad Sci USA 89: 10578–10582, 1992Google Scholar
  28. 28.
    Liotta LA, Steeg PS, Stetler-Stevenson WG: Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation. Cell 64: 327–336, 1991Google Scholar
  29. 29.
    Liotta LA, Tryggvason K, Garbisa S, Hart I, Foltz SM, Shafie S: Metastatic potential correlates with enzymatic degradation of basement membrane collagen. Nature 284: 67–68, 1980Google Scholar
  30. 30.
    Nakajima M, Welch D, Belloni PN, Nicholson GL: Degradation of basement membrane type IV collagen and lung subendothelial matrix by rat mammary adenocarcinoma cell clones of differing metastatic potential. Cancer Res 47: 4869–4876, 1987Google Scholar
  31. 31.
    Taverna D, Groner B, Hynes NE: Epidermal growth factor receptor, platelet-derived growth factor, anderbB-2 receptor activation all promote growth but have distinctive effects upon mouse mammary epithelial cell differentiationGoogle Scholar
  32. 32.
    Bacus SS, Kiguchi K, Chin D, King CR, Huberman E: Differentiation of cultured human breast cancer cells (AU-565 and MCF-7) associated with loss of cell surface HER-2/neu antigen. Mol Carcinog 3: 350–362, 1990Google Scholar
  33. 33.
    Bacus SS, Huberman E, Chin D, Kiguchi K, Simpson S, Lippman M, Lupu R: A ligand for theerbB-2 oncogene product (gp30) induces differentiation of human breast cancer cells. Cell Growth Differ 3(7): 401–411, 1992Google Scholar
  34. 34.
    Takeichi M: Cadherin cell adhesion receptors as a morphogenetic regulator. Science 251: 1451–1455, 1991Google Scholar
  35. 35.
    Sommers CL, Thompson EW, Torri JA, Kemler R, Gelmann EP, Byers SW: Cell adhesion molecule uvomorulin expression in human breast cancer cell lines: relationship to morphology and invasive capacities. Cell Growth and Diff 2: 365–372, 1991Google Scholar
  36. 36.
    Ozawa M, Ringwald M, Kemler R: Uvomurolin-catenin complex formation is regulated by a specific domain in the cytoplasmatic region of the cell adhesion molecule. Proc Natl Acad Sci USA 87: 4246–4250, 1990Google Scholar
  37. 37.
    Behrens J, Vakaet L, Friis R, Winterhager E, Van Roy F, Mareel MM, Birchmeier W: Loss of epithelial differentiation and gain of invasiveness correlates with tyrosine phosphorylation of the E-cadherin/beta-catenin complex in cells transformed with a temperature-sensitive v-SRC gene. J Cell Biol 120: 757–766, 1993Google Scholar
  38. 38.
    Matsuyoshi N, Michinari H, Tanuguchi S, Nagafuchi A, Tsukita S, Takeichi M: Cadherin mediated cell-cell adhesion is perturbed by v-src tyrosine phosphorylation in metastatic fibroblasts. J Cell Biol 118: 703–714, 1992Google Scholar
  39. 39.
    Radler-Pohl A, Gebel S, Sachsenmaier C, Koenig H, Kraemer M, Oehler T, Streile M, Ponta H, Rapp U, Rahmsdorf HJ, Cato ACB, Angel P, Herrlich P: The activation and activity control of AP-1 (fos/jun). Ann NY Acad of Sciences 684: 127–148, 1993Google Scholar
  40. 40.
    Curran T, Franza BR: Fos and jun: The AP-1 connection. Cell 55: 395–397Google Scholar
  41. 41.
    Angel P, Karin M: The role of Jun, Fos and the AP-1 complex in cell proliferation and transformation. Biochem Biophys Acta 1072: 129–157, 1991Google Scholar
  42. 42.
    Ryder K, Nathans D: Induction of protooncogene c-jun by serum growth factors. Proc Natl Acad Sci USA 85: 8464–8467Google Scholar
  43. 43.
    Kovary K, Bravo R: The Jun and Fos protein families are both required for cell cycle progression in fibroblasts. Mol Cell Biol 11: 4466–4472, 1991Google Scholar
  44. 44.
    Sherman ML, Stone R, Datta R, Bernstein S, Kufe DW: Transcriptional and posttranscriptional regulation of c-jun expression during monocytic differentiation of human myeloid leukemic cells. J Biol Chem 265: 3320–3323, 1990Google Scholar
  45. 45.
    Jehn R, Salmons B, Muellner D, Groner B: Overexpression of mos, ras, src, and fos inhibits mouse mammary epithelial cell differentiation. Mol Cell Biol 12: 3890–3902, 1992Google Scholar
  46. 46.
    Lassar AB, Thayer MJ, Overell RW, Weintraub H: Transformation by activated ras and fos prevents myogenesis by inhibiting expression of MyoD1. Cell 58: 659–667, 1989Google Scholar
  47. 47.
    Earl HM, McIlhinney RA, Wilson P, Gusterson BA, Coombes RC: Immunohistochemical study of β- and K-casein in the human breast and breast carcinomas, using monoclonal antibodies. Cancer Res 49: 6070–6076, 1989Google Scholar
  48. 48.
    Shore EM, Nelson WJ: Biosynthesis of the cell adhesion molecule uvomorulin (E-cadherin) in Madin-Darby canine kidney epithelial cells. J Biol Chem 266: 19672, 1991Google Scholar

Copyright information

© Kluwer Academic Publishers 1994

Authors and Affiliations

  • A. Staebler
    • 1
  • C. Sommers
    • 1
  • S. C. Mueller
    • 1
  • S. Byers
    • 1
  • E. W. Thompson
    • 1
  • R. Lupu
    • 1
  1. 1.V.T. Lombardi Cancer Research CenterGeorgetown University Medical CenterWashington, DCUSA

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