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PMID: 7912564 Published · ppublish English Comparative Study Journal Article Review

Epidermal growth factor-related peptides in the pathogenesis of human breast cancer.

Breast cancer research and treatment ·Vol. 29 ·No. 1 ·1994-01-00 ·Pages 11-27

Normanno N, Ciardiello F, Brandt R, Salomon DS

Abstract

A number of different epidermal growth factor (EGF)-related peptides such as EGF, transforming growth factor alpha (TGF alpha), amphiregulin (AR), heregulin (HRG), and cripto-1 (CR-1), are coexpressed to varying degrees in both normal and malignant mammary epithelial cells. However, in general the frequency and level of expression of TGF alpha, AR, and CR-1 are higher in malignant breast epithelial cells than in normal mammary epithelium. In addition, several of these peptides such as TGF alpha and AR can function as autocrine and/or juxtacrine growth factors in mammary epithelial cells, and their expression is stringently regulated by mammotrophic hormones such as estrogens, activated proto-oncogenes that have been implicated in the pathogenesis of breast cancer, and other growth factors. The redundancy of expression that is observed for a number of these structurally related peptides in both normal and malignant mammary epithelial cells suggests that some of these peptides may be involved in regulating other aspects of cellular behavior such as differentiation in addition to proliferation.

MeSH Terms
Amino Acid Sequence Amphiregulin Biomarkers, Tumor Breast/metabolism Breast Neoplasms/metabolism,pathology,physiopathology EGF Family of Proteins Epidermal Growth Factor/biosynthesis,chemistry Epithelium/metabolism ErbB Receptors/analysis,metabolism Female GPI-Linked Proteins Glycoproteins/biosynthesis,chemistry Growth Substances/biosynthesis,chemistry Humans Intercellular Signaling Peptides and Proteins Membrane Glycoproteins Molecular Sequence Data Neoplasm Proteins/biosynthesis,chemistry Neuregulins Protein Structure, Secondary Proto-Oncogene Proteins/analysis,metabolism Receptor, ErbB-2 Transforming Growth Factor alpha/biosynthesis,chemistry
Chemicals
AREG protein, human Amphiregulin Biomarkers, Tumor EGF Family of Proteins GPI-Linked Proteins Glycoproteins Growth Substances Intercellular Signaling Peptides and Proteins Membrane Glycoproteins Neoplasm Proteins Neuregulins Proto-Oncogene Proteins TDGF1 protein, human Transforming Growth Factor alpha Epidermal Growth Factor ErbB Receptors Receptor, ErbB-2
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Normanno N
Tumor Growth Factor Section, Laboratory of Tumor Immunology and Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Ciardiello F
Brandt R
Salomon D S
References (95)
95 references, click to expand
  1. Expression of transforming growth factor alpha (TGF alpha) in differentiated rat mammary tumors: estrogen induction of TGF alpha production.
    Mol Endocrinol. 1987 Oct;1(10):683-92 PMID: 2484711
  2. Amphiregulin messenger RNA is elevated in psoriatic epidermis and gastrointestinal carcinomas.
    Cancer Res. 1992 Jun 1;52(11):3224-7 PMID: 1591731
  3. Transforming growth factor alpha in human mammary carcinomas and their metastases.
    Anticancer Res. 1989 Jan-Feb;9(1):177-9 PMID: 2705746
  4. Immunohistochemical demonstration of growth factors, TGF-alpha, TGF-beta, IGF-I and neu oncogene product in benign and malignant human breast tissues.
    Anticancer Res. 1990 Sep-Oct;10(5A):1115-26 PMID: 1978632
  5. Expression of transforming growth factor alpha antisense mRNA inhibits the estrogen-induced production of TGF alpha and estrogen-induced proliferation of estrogen-responsive human breast cancer cells.
    J Cell Physiol. 1993 Sep;156(3):497-514 PMID: 8360257
  6. Transforming growth factor alpha production and epidermal growth factor receptor expression in normal and oncogene transformed human mammary epithelial cells.
    Mol Endocrinol. 1989 Jan;3(1):203-14 PMID: 2783757
  7. Local effects of EGF, alpha-TGF, and EGF-like growth factors on lobuloalveolar development of the mouse mammary gland in vivo.
    J Cell Physiol. 1987 Sep;132(3):581-4 PMID: 3498730
  8. Transcripts for transforming growth factors in human breast cancer: clinical correlates.
    Br J Cancer. 1990 Apr;61(4):612-7 PMID: 2331446
  9. The prognostic significance of transforming growth factors in human breast cancer.
    Br J Cancer. 1993 Jun;67(6):1408-12 PMID: 8390290
  10. Heterodimerization of the erbB-1 and erbB-2 receptors in human breast carcinoma cells: a mechanism for receptor transregulation.
    Biochemistry. 1990 Dec 18;29(50):11024-8 PMID: 1980216
  11. Increased expression of growth factor mRNAs accompanies viral transformation of rodent cells.
    Oncogene Res. 1988;2(2):135-48 PMID: 3217109
  12. Epidermal growth factor receptor, but not c-erbB-2, activation prevents lactogenic hormone induction of the beta-casein gene in mouse mammary epithelial cells.
    Mol Cell Biol. 1990 Aug;10(8):4027-34 PMID: 2196443
  13. Autocrine interaction between TGF alpha and the EGF-receptor: quantitative requirements for induction of the malignant phenotype.
    Oncogene. 1989 Jul;4(7):831-8 PMID: 2755700
  14. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene.
    Science. 1987 Jan 9;235(4785):177-82 PMID: 3798106
  15. Expression of transforming growth factor alpha, amphiregulin and cripto-1 in human breast carcinomas.
    Br J Cancer. 1994 May;69(5):903-10 PMID: 8180021
  16. Growth factors and cancer.
    Cancer Res. 1986 Mar;46(3):1015-29 PMID: 3002607
  17. Regulation of transforming growth factor alpha and transforming growth factor beta messenger ribonucleic acid abundance in T-47D, human breast cancer cells.
    Mol Endocrinol. 1989 Apr;3(4):611-7 PMID: 2524651
  18. Ligand-specific activation of HER4/p180erbB4, a fourth member of the epidermal growth factor receptor family.
    Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1746-50 PMID: 8383326
  19. The amphiregulin gene encodes a novel epidermal growth factor-related protein with tumor-inhibitory activity.
    Mol Cell Biol. 1990 May;10(5):1969-81 PMID: 2325643
  20. Isolation of the neu/HER-2 stimulatory ligand: a 44 kd glycoprotein that induces differentiation of mammary tumor cells.
    Cell. 1992 Apr 3;69(1):205-16 PMID: 1348215
  21. Role of transforming growth factor-alpha-related peptides in the autocrine/paracrine control of experimental breast cancer growth in vitro by estradiol, prolactin, and progesterone.
    Breast Cancer Res Treat. 1990 Feb;15(2):73-83 PMID: 2322651
  22. Heparin inhibition of autonomous growth implicates amphiregulin as an autocrine growth factor for normal human mammary epithelial cells.
    J Cell Physiol. 1992 Oct;153(1):103-11 PMID: 1522124
  23. ARIA, a protein that stimulates acetylcholine receptor synthesis, is a member of the neu ligand family.
    Cell. 1993 Mar 12;72(5):801-15 PMID: 8453670
  24. Amphiregulin induces tyrosine phosphorylation of the epidermal growth factor receptor and p185erbB2. Evidence that amphiregulin acts exclusively through the epidermal growth factor receptor at the surface of human epithelial cells.
    J Biol Chem. 1993 Feb 5;268(4):2924-31 PMID: 7679104
  25. Transforming growth factors in human breast cancer.
    Biomed Pharmacother. 1989;43(9):661-7 PMID: 2624883
  26. Transforming growth factor-alpha: an oncodevelopmental growth factor.
    Cancer Cells. 1990 Dec;2(12):389-97 PMID: 2088454
  27. Computer-based characterization of epidermal growth factor precursor.
    Nature. 1984 Feb 9-15;307(5951):558-60 PMID: 6607417
  28. Differentiation of cultured human breast cancer cells (AU-565 and MCF-7) associated with loss of cell surface HER-2/neu antigen.
    Mol Carcinog. 1990;3(6):350-62 PMID: 1980588
  29. Amphiregulin as an autocrine growth factor for c-Ha-ras- and c-erbB-2-transformed human mammary epithelial cells.
    Proc Natl Acad Sci U S A. 1994 Mar 29;91(7):2790-4 PMID: 7908443
  30. Immunoreactive alpha transforming growth factor activity in effusions from cancer patients as a marker of tumor burden and patient prognosis.
    Cancer Res. 1988 Sep 1;48(17):5023-8 PMID: 3165707
  31. The interaction of amphiregulin with nuclei and putative nuclear localization sequence binding proteins.
    Growth Factors. 1992;7(4):305-14 PMID: 1306686
  32. Presence of transforming growth factors in human breast cancer cells.
    Cancer Res. 1984 Sep;44(9):4069-77 PMID: 6331663
  33. Transforming growth factor-alpha expression is enhanced in human mammary epithelial cells transformed by an activated c-Ha-ras protooncogene but not by the c-neu protooncogene, and overexpression of the transforming growth factor-alpha complementary DNA leads to transformation.
    Cell Growth Differ. 1990 Sep;1(9):407-20 PMID: 1981145
  34. Down-regulation of transforming growth factor-alpha by tamoxifen in human breast cancer.
    Cancer. 1993 Jul 1;72(1):131-6 PMID: 8508397
  35. Expression of cripto, a novel gene of the epidermal growth factor gene family, leads to in vitro transformation of a normal mouse mammary epithelial cell line.
    Cancer Res. 1991 Feb 1;51(3):1051-4 PMID: 1846316
  36. Direct interaction of a ligand for the erbB2 oncogene product with the EGF receptor and p185erbB2.
    Science. 1990 Sep 28;249(4976):1552-5 PMID: 2218496
  37. Characterization of a growth factor that binds exclusively to the erbB-2 receptor and induces cellular responses.
    Proc Natl Acad Sci U S A. 1992 Mar 15;89(6):2287-91 PMID: 1347947
  38. Expression in rat fibroblasts of a human transforming growth factor-alpha cDNA results in transformation.
    Cell. 1986 Jul 18;46(2):301-9 PMID: 3459590
  39. Expression of amphiregulin, cripto-1, and heregulin-alpha in human breast-cancer cells.
    Int J Oncol. 1993 Jun;2(6):903-11 PMID: 21573645
  40. Immunological detection and quantitation of alpha transforming growth factors in human breast carcinoma cells.
    Breast Cancer Res Treat. 1986;7(3):201-10 PMID: 3465381
  41. Neu differentiation factor: a transmembrane glycoprotein containing an EGF domain and an immunoglobulin homology unit.
    Cell. 1992 May 1;69(3):559-72 PMID: 1349853
  42. Expression of neu protein, epidermal growth factor receptor, and transforming growth factor alpha in breast cancer. Correlation with clinicopathologic parameters.
    Am J Pathol. 1991 Jun;138(6):1527-34 PMID: 1711294
  43. Transforming growth factor alpha.
    Cell. 1988 Aug 26;54(5):593-5 PMID: 3044605
  44. Identification of an estrogen response element in the 3'-flanking region of the murine c-fos protooncogene.
    J Biol Chem. 1992 Sep 5;267(25):18047-54 PMID: 1517237
  45. Structure and function of human amphiregulin: a member of the epidermal growth factor family.
    Science. 1989 Feb 24;243(4894 Pt 1):1074-6 PMID: 2466334
  46. Overexpression of TGF alpha in transgenic mice: induction of epithelial hyperplasia, pancreatic metaplasia, and carcinoma of the breast.
    Cell. 1990 Jun 15;61(6):1121-35 PMID: 1693546
  47. Human epidermal growth factor receptor cDNA sequence and aberrant expression of the amplified gene in A431 epidermoid carcinoma cells.
    Nature. 1984 May 31-Jun 6;309(5967):418-25 PMID: 6328312
  48. Expression and functional properties of transforming growth factor alpha and epidermal growth factor during mouse mammary gland ductal morphogenesis.
    Proc Natl Acad Sci U S A. 1991 Jan 1;88(1):276-80 PMID: 1986376
  49. Identification of heregulin, a specific activator of p185erbB2.
    Science. 1992 May 22;256(5060):1205-10 PMID: 1350381
  50. Partial purification of transforming growth factors from human milk.
    Cancer Res. 1986 Feb;46(2):933-9 PMID: 3000589
  51. Molecular characterization of a gene of the 'EGF family' expressed in undifferentiated human NTERA2 teratocarcinoma cells.
    EMBO J. 1989 Jul;8(7):1987-91 PMID: 2792079
  52. Cellular and viral ligands that interact with the EGF receptor.
    Semin Cancer Biol. 1990 Aug;1(4):257-63 PMID: 2103500
  53. Modulation by estrogen and growth factors of transforming growth factor-alpha and epidermal growth factor receptor expression in normal and malignant human mammary epithelial cells.
    Recent Results Cancer Res. 1989;113:57-69 PMID: 2756237
  54. Isolation and characterization of ERBB3, a third member of the ERBB/epidermal growth factor receptor family: evidence for overexpression in a subset of human mammary tumors.
    Proc Natl Acad Sci U S A. 1989 Dec;86(23):9193-7 PMID: 2687875
  55. Purification and characterization of the neu/erb B2 ligand-growth factor from bovine kidney.
    J Biol Chem. 1992 Jun 5;267(16):11508-12 PMID: 1350785
  56. Transformation of mouse mammary epithelial cells with the Ha-ras but not with the neu oncogene results in a gene dosage-dependent increase in transforming growth factor-alpha production.
    FEBS Lett. 1989 Jul 3;250(2):474-8 PMID: 2568949
  57. Response to and expression of amphiregulin by ovarian carcinoma and normal ovarian surface epithelial cells: nuclear localization of endogenous amphiregulin.
    Biochem Biophys Res Commun. 1991 Oct 31;180(2):481-8 PMID: 1953719
  58. Human transforming growth factor-alpha: precursor structure and expression in E. coli.
    Cell. 1984 Aug;38(1):287-97 PMID: 6088071
  59. Amphiregulin, epidermal growth factor receptor, and estrogen receptor expression in human primary breast cancer.
    Cancer Res. 1993 Aug 1;53(15):3597-602 PMID: 8101763
  60. Transforming growth factor alpha in epithelial proliferative diseases of the breast.
    J Clin Pathol. 1992 Jun;45(6):513-6 PMID: 1320636
  61. Glial growth factors are alternatively spliced erbB2 ligands expressed in the nervous system.
    Nature. 1993 Mar 25;362(6418):312-8 PMID: 8096067
  62. Induction of transforming growth factor alpha expression in mouse mammary epithelial cells after transformation with a point-mutated c-Ha-ras protooncogene.
    Mol Endocrinol. 1988 Dec;2(12):1202-16 PMID: 3063955
  63. Isolation and characterization of the CRIPTO autosomal gene and its X-linked related sequence.
    Am J Hum Genet. 1991 Sep;49(3):555-65 PMID: 1882841
  64. Tumor-inhibitory monoclonal antibodies to the HER-2/Neu receptor induce differentiation of human breast cancer cells.
    Cancer Res. 1992 May 1;52(9):2580-9 PMID: 1373672
  65. Differential growth factor expression in transformed mouse NIH-3T3 cells.
    J Cell Biochem. 1990 Jan;42(1):45-57 PMID: 1967612
  66. Transforming growth factor-alpha messenger RNA localization in the developing adult rat and human mammary gland by in situ hybridization.
    Dev Biol. 1990 Jul;140(1):123-31 PMID: 2358112
  67. Autocrine secretion--10 years later.
    Ann Intern Med. 1992 Sep 1;117(5):408-14 PMID: 1503333
  68. Immunohistochemical studies on oncogene products (EGF-R, c-erbB-2) and growth factors (EGF, TGF-alpha) in human breast cancer: their relationship to oestrogen receptor status, histological grade, mitotic index and nodal status.
    Virchows Arch A Pathol Anat Histopathol. 1992;420(4):345-51 PMID: 1348890
  69. Cell-type specific interaction of Neu differentiation factor (NDF/heregulin) with Neu/HER-2 suggests complex ligand-receptor relationships.
    EMBO J. 1993 Mar;12(3):961-71 PMID: 8096177
  70. TGF alpha and TGF beta expression in mammary carcinoma.
    J Pathol. 1993 May;170(1):15-22 PMID: 8392105
  71. Purification and characterization of a novel growth factor from human breast cancer cells.
    Biochemistry. 1992 Aug 18;31(32):7330-40 PMID: 1324710
  72. Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene.
    Science. 1985 Dec 6;230(4730):1132-9 PMID: 2999974
  73. Retinoic acid induces neuronal differentiation of a cloned human embryonal carcinoma cell line in vitro.
    Dev Biol. 1984 Jun;103(2):285-93 PMID: 6144603
  74. A heparin sulfate-regulated human keratinocyte autocrine factor is similar or identical to amphiregulin.
    Mol Cell Biol. 1991 May;11(5):2547-57 PMID: 2017164
  75. Correlation of HER-2/neu amplification with expression and with other prognostic factors in 1103 breast cancers.
    J Natl Cancer Inst. 1992 Aug 19;84(16):1279-82 PMID: 1353538
  76. Growth factors and cancer.
    Science. 1991 Nov 22;254(5035):1146-53 PMID: 1659742
  77. Vaccinia virus encodes a polypeptide homologous to epidermal growth factor and transforming growth factor.
    Nature. 1985 Feb 7-13;313(6002):491-2 PMID: 3871510
  78. Development of mammary hyperplasia and neoplasia in MMTV-TGF alpha transgenic mice.
    Cell. 1990 Jun 15;61(6):1147-55 PMID: 2161707
  79. Regulation by estrogen through the 5'-flanking region of the transforming growth factor alpha gene.
    Mol Endocrinol. 1991 Dec;5(12):1955-63 PMID: 1791840
  80. A 25 kDa polypeptide is the ligand for p185neu and is secreted by activated macrophages.
    Oncogene. 1991 Dec;6(12):2187-96 PMID: 1685016
  81. Transformation of an established mouse mammary epithelial cell line following transfection with a human transforming growth factor alpha cDNA.
    Mol Carcinog. 1989;2(1):1-11 PMID: 2786419
  82. Biologically active precursor for transforming growth factor type alpha, released by retrovirally transformed cells.
    Proc Natl Acad Sci U S A. 1986 Sep;83(17):6307-11 PMID: 3018723
  83. Neural expression and chromosomal mapping of Neu differentiation factor to 8p12-p21.
    Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1867-71 PMID: 8095334
  84. Characterization of a neu/c-erbB-2 protein-specific activating factor.
    Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8582-6 PMID: 1717981
  85. Signal transduction by receptors with tyrosine kinase activity.
    Cell. 1990 Apr 20;61(2):203-12 PMID: 2158859
  86. mRNA expression of transforming growth factor alpha in human breast carcinomas and its activity in effusions of breast cancer patients.
    J Natl Cancer Inst. 1989 Aug 2;81(15):1165-71 PMID: 2545892
  87. Expression of the transforming growth factor-alpha/epidermal growth factor receptor pathway in normal human breast epithelial cells.
    Endocrinology. 1990 Jan;126(1):596-607 PMID: 2294006
  88. TGF alpha overexpression in transgenic mice induces liver neoplasia and abnormal development of the mammary gland and pancreas.
    Cell. 1990 Jun 15;61(6):1137-46 PMID: 2350785
  89. Epidermal and transforming growth factor alpha in patients with breast tumours.
    Br J Cancer. 1989 Apr;59(4):605-9 PMID: 2785399
  90. Expression of transforming growth factor alpha and its messenger ribonucleic acid in human breast cancer: its regulation by estrogen and its possible functional significance.
    Mol Endocrinol. 1988 Jun;2(6):543-55 PMID: 3047554
  91. Transforming growth factor-alpha. A model for membrane-anchored growth factors.
    J Biol Chem. 1990 Dec 15;265(35):21393-6 PMID: 2254298
  92. Amphiregulin: a bifunctional growth-modulating glycoprotein produced by the phorbol 12-myristate 13-acetate-treated human breast adenocarcinoma cell line MCF-7.
    Proc Natl Acad Sci U S A. 1988 Sep;85(17):6528-32 PMID: 3413110
  93. Growth factor expression in normal, benign, and malignant breast tissue.
    Br Med J (Clin Res Ed). 1988 Jun 11;296(6637):1621-4 PMID: 3135043
  94. Differential immunohistochemical detection of amphiregulin and cripto in human normal colon and colorectal tumors.
    Cancer Res. 1992 Jun 15;52(12):3467-73 PMID: 1596904
  95. Infection with a TGF-alpha retroviral vector transforms normal mouse mammary epithelial cells but not normal rat fibroblasts.
    Oncogene. 1989 Nov;4(11):1375-82 PMID: 2812779
Article Info
Journal
Breast cancer research and treatment
Abbr.
Breast Cancer Res Treat
ISSN
0167-6806
DOI
10.1007/BF00666178
Published
1994-01-00
Pages
11-27
Language
English
Region
Netherlands
NLM ID
8111104
Subset
IM
External Links
PubMed source DOI: 10.1007/BF00666178 View journal details
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