Skip to main content
Log in

Insulin-like growth factor mediated stromal-epithelial interactions in human breast cancer

  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

The prominent ‘desmoplastic’ or stromal reaction seen in many invasive breast carcinomas lead to early speculation that stromal cells play a role in breast cancer pathogenesis [1]. Experimental evidence now supports this hypothesis and interactions between stromal cells and epithelial cells appear to be important for both normal mammary development and neoplasia. The identification of genes that are selectively expressed in the stroma of malignant breast lesions has recently provided new insights into the molecular basis of stromal-epithelial interactions. Stromally expressed genes include growth factors, proteases and extracellular matrix proteins, all biological activities with potential roles in malignant progression. Investigations discussed here concern the nature of the paracrine signals provided by malignant epithelial cells that activate changes in stromal gene expression, the effect that the stromally derived factors have on the behavior of malignant epithelial cells and the identification of novel factors and receptors in either stroma or epithelia that contribute to their mutual interactions. These questions will be addressed in the context of this laboratory's studies on insulin-like growth factors, as these molecules show marked differences in stromal expression between benign and malignant breast tissue and thus provide a useful paradigm for investigations into the paracrine environment of an evolving breast tumor.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Van den Hooff A: Stromal involvement in malignant growth. Adv Canc Res 50: 159–195, 1991

    Google Scholar 

  2. Cullen KJ, Lippman ME: Stromal-epithelial interactions in breast cancer. Cancer Treat Res 61: 413–431, 1992

    Google Scholar 

  3. Basset P, Bellocq JP, Wolf C, Stoll I, Hutin P, Limacher JM, Podhajcer OL, Chenard MP, Rio MC, Chambon P: A novel metalloproteinase gene specifically expressed in stromal cells of breast carcinomas. Nature 348: 699–704, 1990

    Google Scholar 

  4. Blundell TL, Humbel RE: Hormone families: pancreatic hormones and homologous grouwth factors. Nature 287: 781–787, 1980

    Google Scholar 

  5. Humbel RE: Insulin-like growth factors I and II. Eur J Biochem 190: 445–462, 1990

    Google Scholar 

  6. Cohick WS, Clemmons DR: The Insulin-like growth factors. Annu Rev Physiol 55: 131–153, 1993

    Google Scholar 

  7. Voss JW, Rosenfeld MG: Anterior pituitary development: short tails from dwarf mice. Cell 70: 527–530, 1990

    Google Scholar 

  8. Liu JP, Baker J, Perkins AS, Robertson EJ, Efstratiadis A: Mice carrying null mutations of the genes encoding insulin-like growth factor (igf-I) and type I IGF receptor (igf-Ir). Cell 75: 59–72, 1993

    Google Scholar 

  9. De Chiara TM, Efstratiadis A: A growth deficiency phenotype in heterozygous mice carrying an insulin-like growth factor II gene disrupted by targeting. Nature 345: 78–80, 1990

    Google Scholar 

  10. Baker J, Liu JP, Robertson EJ, Efstratiadis A: Role of insulin-like growth factors in embryonic and postnatal growth. Cell 75: 73–82, 1993

    Google Scholar 

  11. Nissley SP, Rechler MM: Insulin-like growth factors: biosynthesis, receptors, and carrier proteins. Hormonal Proteins and Peptides 12: 127–203, 1986

    Google Scholar 

  12. Unterman TG, Simmons RA, Glick RP, Ogata ES: Circulating levels of insulin, insulin-like growth factor-I (IGF-I), IGF-II, and IGF-binding proteins in the small for gestational age fetal rat. Endocrinology 132 (1): 327–336, 1993

    Google Scholar 

  13. Gluckman PD, Ambler GR: What is the function of circulating insulin-like growth factor-2 in postnatal life? Mol Cell Endocrinol 92 (1): C1-C3, 1993

    Google Scholar 

  14. Schofield PN, Tate VE: Regulation of human IGF-II transcription in fetal and adult tissues. Development 101: 793–803, 1987

    Google Scholar 

  15. D'Ercole AJ, Stiles AD, Underwood LE: Tissue concentrations of somatomedin CL; Further evidence for multiple sites of synthesis and paracrine or autocrine mechanisms of action. Proc Natl Acad Sci USA 81: 935–939, 1984

    Google Scholar 

  16. Reeve AE, Eccles MR, Wilkins RJ, Bell GI, Millow LJ: Expression of insulin-like growth factor II transcripts in Wilm's tumor. Nature 317: 258–260, 1985

    Google Scholar 

  17. Nielsen FC, Haselbacher G, Christiansen J, Lake M, Gronborg M, Gammeltoft S: Biosynthesis of 10 kDa and 7.5 kDa insulin-like growth factor II in a human Rhabdomyosarcoma cell line. Mol Cell Endocrinol 93 (1): 87–95, 1993

    Google Scholar 

  18. Drummond IA, Madden SL, Rohwer-Nutter P, Bell GI, Sukhatme VP, Rauscher FJ III: Repression of the insulin-like growth factor II gene by the Wilm's tumor suppressor WT-1. Science 257 (5070): 674–678, 1992

    Google Scholar 

  19. Henry I, Bonaiti-Pellie C, Chehensse V, Beldjord C, Schwartz C, Utermann G, Junien C: Uniparental paternal disomy in a genetic cancer-predisposing syndrome. Nature 351: 665–667, 1991

    Google Scholar 

  20. De Chiara TM, Robertson EJ, Efstradiadis A: Parental imprinting of the mouse insulin-like growth factor II gene. Cell 64: 849–859, 1991

    Google Scholar 

  21. Giannoukakis N, Deal C, Paquette J, Goodyer CG, Polychronakos C: Parental genomic imprinting of the human IGF2 gene. Nat Genet 4 (1): 98–101, 1993

    Google Scholar 

  22. Rainier S, Johnson LA, Dobry CJ, Ping AJ, Grundy PE, Feinberg AP: Relaxation of imprinted genes in human cancer. Nature 362 (6422): 747–749, 1993

    Google Scholar 

  23. Ogawa O, Eccles MR, Szeto J, McNoe LA, Yun K, Maw MA, Smith PJ, Reeve AE: Relaxation of insulin-like growth factor II gene imprinting implicated in Wilm's tumour. Nature 362 (6422): 749–751, 1993

    Google Scholar 

  24. Reeve JG, Brinkman A, Hughes S, Mitchell J, Schwander J, Bleehan NM: Expression of Insulin-like growth factor (IGF) and IGF-binding protein genes in human lung tumor cell lines. J Natl Cancer Institute 84: 628–634, 1992

    Google Scholar 

  25. Su T-S, Liu W-Y, Han S-H, Jansen M, Yang-Fen TL, P'eng F-K, Chou C-K: Transcripts of the insulin-like growth factors I and II in human hepatoma. Cancer Res 49: 1773–1777, 1989

    Google Scholar 

  26. Tricoli JV, Rall LB, Karakousis CP: Enhanced levels of insulin-like growth factor messenger RNA in human colon carcinomas and liposarcomas. Cancer Res 46: 6169–6173, 1986

    Google Scholar 

  27. Yee D, Cullen KJ, Paik S, Perdue JF, Hampton B, Schwartz A, Lippman ME, Rosen N: Insulin-like growth factor II mRNA expression in human breast cancer. Cancer Res 48: 6691–6696, 1988

    Google Scholar 

  28. Harbour JW, Lai SL, Whang-Pen J: Abnormalities in structure and expression of the human retinoblastoma gene in SCLC. Science 241: 353–357, 1988

    Google Scholar 

  29. Varley JM, Armour J, Swallow JE: The retinoblastoma gene is frequently altered leading to loss of expression in primary breast cancers. Oncogene 4: 725–729, 1989

    Google Scholar 

  30. Cullen KJ, Lippman ME: Estrogen regulation of protein synthesis and cell growth in human breast cancer. Vitam Horm 45: 127–172, 1989

    Google Scholar 

  31. Yee D, Favoni RE, Lebovic GS, Lombana F, Powell DR, Reynolds CP, Rosen N: Insulin-like growth factor I expression of tumors of neuroectodermal origin with the t(11;22) chromosomal translocation. J Clin Invest 86: 1806–1814, 1990

    Google Scholar 

  32. Sandberg AC, Enberg C, Lake M, Von Holst H, Sara VR: The expression of IGF-I and IGF-II genes in the human fetal and adult brain and glioma. Neuroscience Letts 93 (1): 114–119, 1990

    Google Scholar 

  33. Yee D, Morales FR, Hamilton TC, Von Hoff DD: Expression of Insulin-like growth factor I, its binding proteins, and its receptor in ovarian cancer. Cancer Res 51: 5107–5112, 1991

    Google Scholar 

  34. Nilsson O, Wangberg B, Theodorsson E, Skottner A, Ahlman H: Presence of IGF-I in human midgut carcinoid tumors- an antocrine regulator of carcinoid tumor growth? Int J Cancer 51 (2): 195–203, 1992

    Google Scholar 

  35. Osborne CK, Coronado EB, Kitten LJ, Arteaga CI, Fuqua SA, Ramasharma K, Marshall M, Li CH: Insulin-like growth factor-II (IGF-II): a potential autocrine/paracrine growth factor for human breast cancer acting via the IGF-I receptor. Mol Endo 3: 1701–1709, 1989

    Google Scholar 

  36. Cullen KJ, Yee D, Sly WS, Perdue J, Hampton B, Lippman ME, Rosen N: Insulin-like growth factor receptor expression and function in human breast cancer. Cancer Res 50 (1): 48–53, 1990

    Google Scholar 

  37. Thorson T, Lahooti H, Rasmussen M, Aakvaag A: Oestrodiol treatment increases the sensitivity of MCF-7 cells for the growth stimulatory effect of IGF-I. J Steroid Biochem Mol Biol 41 (3-8): 537–540, 1992

    Google Scholar 

  38. Stewart AJ, Johnson MD, May FEB, Westley BR: Role of insulin-like growth factors and type I insulin-like growth factor receptor in the estrogen stimulated proliferation of human breast cancer cells. J Biol Chem 265: 31172–31178, 1990

    Google Scholar 

  39. Yee D, Paik S, Lebovic GS, Marcus RR, Favoni RE, Cullen KJ, Lippman ME, Rosen N: Analysis of insulin-like growth factor I gene expression in malignancy: evidence for a paracrine role in human breast cancer. Mol Endocrinol 3 (3): 509–517, 1989

    Google Scholar 

  40. Paik S: Expression of IGF-I and IGF-II mRNA in breast tissue. Breast Cancer Res Treat 22 (1): 31–38, 1992

    Google Scholar 

  41. Cullen KJ, Smith HS, Hill S, Rosen N, Lippman ME: Growth factor messenger RNA expression by human breast fibroblasts from benign and malignant lesions. Cancer Res 51 (18): 4978–4985, 1991

    Google Scholar 

  42. Singer C, Smith HS, Lippman ME, Cullen KJ: IGF-I and IGF-II expression in fibroblasts derived from tumor, normal breast and skin of breast cancer patients. J Cell Biochem 16D: CC315, 1992

    Google Scholar 

  43. Chiquet-Ehrismann R, Kalla P, Pearson CA: Participation of tenascin and transforming growth factor-β in reciprocal epithelial-mesenchymal interactions of MCF7 cells and fibroblasts. Cancer Res 49: 4322–4325, 1989

    Google Scholar 

  44. Singer C, Cullen KJ: Manuscript in preparation

  45. Bronzert DA, Pantazis P, Antoniades HN, Kasid A, Davidson N, Dickson RB, Lippman ME: Synthesis and secretion of platelet derived growth factor by human breast cancer cell lines. Proc Natl Acad Sci USA 84: 5763–5767, 1987

    Google Scholar 

  46. Clemmons DR: Multiple hormones stimulate the production of somatomedin by cultured human fibroblasts. J Clin Endocrinol Metab 58: 850–856, 1984

    Google Scholar 

  47. Horgan K, Jones DL, Mansel RE: Mitogenicity of human fibroblastsin vivo for human breast cancer cells. Br J Surg 74: 227–229, 1987

    Google Scholar 

  48. Talts JF, Aufderheiden E, Sorokin L, Ocklind G, Mattsson R, Ekblom P: Induction of mouse tenascin by a human sarcomatoid Wilm's tumor cell line growing in nude mice. Int J Can 54: 868–874, 1993

    Google Scholar 

  49. Cullen KJ, Lippman ME, Chow D, Hill S, Rosen N, Zwiebel JA: Insulin-like growth factor-II overexpression in MCF-7 cells induces phenotypic changes associated with malignant progression. Mol Endocrinol 6 (1): 91–100, 1992

    Google Scholar 

  50. Daly RJ, Harris WH, Wang DY, Darbre PD: Autocrine production of insulin-like growth factor II using an inducible expression system results in reduced estrogen sensitivity of MCF-7 human breast cancer cells. Cell Growth Differen 2: 457–464, 1991

    Google Scholar 

  51. Krywici RF, Yee D: The insulin-like growth factor family of ligands, receptors and binding proteins. Breast Cancer Res Treat 22: 7–19, 1992

    Google Scholar 

  52. Siddle K: The insulin receptor and type I IGF receptor: Comparison of structure and function. Prog Growth Factor Res 4: 301–320, 1992

    Google Scholar 

  53. Moxham CP, Jacobs S: Insulin/IGF-I receptor hybrids: A mechanism for increasing receptor diversity. J Cell Biochem 48: 136–140, 1992

    Google Scholar 

  54. Baltensperger K, Kozma LM, Cherniack AD, Klarlund JK, Chawla A, Banerjee U, Czech MP: Binding of the Ras activator Son of Sevenless to insulin receptor substrate-I signalling complexes. Science 260: 1950–1952, 1993

    Google Scholar 

  55. Skolnik EY, Batzer A, Li N, Lee C-H, Lowenstein E, Mohammadi M, Margolis B, Schlessinger J: The function of GRB2 in linking the insulin receptor to Ras signaling pathways. Science 260: 1953–1955, 1993

    Google Scholar 

  56. Peyrat JPh, Bonneterre J: Type I IGF receptor in human breast diseases. Breast Cancer Res Treat 22: 59–67, 1992

    Google Scholar 

  57. Berns EMJJ, Klijn JGM, Van Stavaren IL, Portengen H, Foekens JA: Sporadic amplification of the insulin-like growth factor I receptor in human breast tumors. Canc Res 52: 1036–1039, 1992

    Google Scholar 

  58. Papa V, Biancamaria G, Clark GM, McGuire WL, Moore D, Fujita-Yamaguchi Y, Riccardo V, Goldfine ID, Pezzino V: Insulin-like growth factor receptors are overexpressed and predict a low risk in human breast cancer. Canc Res 53: 3736–3740, 1992

    Google Scholar 

  59. Morgan DO, Edman JC, Standring DN, Fried VA, Smith MC, Roth RA, Rutter WJ: Insulin-like growth factor II receptor as a multifunctional binding protein. Nature 329: 301–307, 1987

    Google Scholar 

  60. Vignon F, Rochefort H: Interactions of Pro-cathepsin D and IGF-II on the mannose-6-phosphate/IGF-II receptor. Breast Canc Res Treat 22: 47–57, 1992

    Google Scholar 

  61. Dennis PA, Rifkin DB: Cellular activation of latent transforming growth factor β1 requires binding to the cation-in-dependent mannose-6-phosphate/insulin like growth factor II receptor. Proc Natl Acad Sci USA 88: 580–584, 1991

    Google Scholar 

  62. Barlow DP, Stoger R, Hermann BG, Saito K, Schweifer N: The mouse insulin-like growth factor type 2 receptor is imprinted and closely linked to the Tme locus. Nature 349: 84–87, 1991

    Google Scholar 

  63. Filson AJ, Louvi A, Efstratiadis A, Robertson EJ: Rescue of the T-associated maternal effect in mice carrying null mutations inIgf-2 andIgf-2r, two reciprocally imprinted genes. Development 118: 731–736, 1993

    Google Scholar 

  64. Nishimoto I, Murayama Y, Katada T, Ui M, Ogata E: Possible direct linkage of insulin-like growth factor-II receptor with guanine nucleotide-binding proteins. J Biol Chem 264 (24): 14029–14038, 1989

    Google Scholar 

  65. Zhoa Y, Escot C, Maudelonde T, Puech C, Rouanet P, Rochefort H: Correlation between Mannose-6-phosphate/IGF-II receptor and Cathepsin D RNA levels byin situ hybridization in benign and malignant mammary tumors. Canc Res 53: 2901–2905, 1993

    Google Scholar 

  66. Jirtle RL, Haag JD, Ariazi EA, Gould MN: Increased Mannose 6-phosphate/insulin-like growth factor II receptor and transforming growth factor β1 levels during monoterpeneinduced regression of mammary tumors. Canc Res 53: 3849–3852, 1993

    Google Scholar 

  67. Pietrzkowski Z, Lammers R, Carpenter G, Soderquist AM, Limardo M, Phillips PD, Ullrich A, Baserga R: Constitutive expression of insulin-like growth factor 1 and insulin-like growth factor 1 receptor abrogates all requirements for exogenous growth factors. Cell Growth Diff 3: 199–205, 1992

    Google Scholar 

  68. Baserga R: IGF-I receptor as the restriction point of the cell cycle. Ann NY Acad Sci 663: 154–157, 1992

    Google Scholar 

  69. Milazzo G, Yip CC, Maddux BA, Vigneri R, Goldfine ID: High affinity Insulin biding to an atypical insulin-like growth factor-I receptor in human breast cancer cells. J Clin Invest 89: 899–908, 1992

    Google Scholar 

  70. Sakana K, Enjoh T, Numata F, Fujiwara H, Marumoto Y, Higashihash N, Sata Y, Perdue J, Fujita-Yamaguchi Y: The design, expression, and characterisation of human Insulin-like growth factor II (IGF-II) mutants specific for either the IGF-II/cation-independent mannose-6-phosphate receptor or IGF-I receptor. J Biol Chem 266: 20626–20635, 1991

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ellis, M.J.C., Singer, C., Hornby, A. et al. Insulin-like growth factor mediated stromal-epithelial interactions in human breast cancer. Breast Cancer Res Tr 31, 249–261 (1994). https://doi.org/10.1007/BF00666158

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00666158

Key words

Navigation