Breast Cancer Research and Treatment

, Volume 41, Issue 1, pp 43–50 | Cite as

IGF-II mRNA and protein are expressed in the stroma of invasive breast cancers: Anin situ hybridization and immunohistochemistry study

  • Claudio Giani
  • Kevin J. Cullen
  • Daniela Campani
  • Audrey Rasmussen
Report

Abstract

Insulin-like growth factor-II (IGF-II) is a potent mitogen for a variety of cell types and is considered an important regulator of breast cancer growth. In this study, we analyzed IGF-II mRNA and protein expression in a series of 80 cases of invasive breast cancer. Seventy-five cases produced informative results for IGF-II mRNA expression, and were scored on an arbitrary scale. Two cases (2.6%) had no significant IGF-II mRNA expression. 35 cases (46.7%) expressed low levels of IGF-II mRNA, 20 cases (26.7%) moderate IGF-II mRNA, while 18 (24%) expressed high levels of IGF-II message. Generally, IGF-II mRNA was expressed in the smooth muscle walls of blood vessels and ducts, as well as in the stroma tightly adjacent to and surrounding tumor epithelium. IGF-II mRNA content was also directly related to the amount of the stroma within the tumor (p<0.05). In 10 cases (13.3%) IGF-II mRNA was detected in the stroma of normal lobules. Fifty-six out of 75 were positive for IGF-II immunostaining. Again, protein staining was generally observed in the smooth muscle of both blood vessels and ducts, as well as in the stroma surrounding tumor epithelium. In normal lobules and ducts the IGF-II protein was detected in the myoepithelium. Unequivocal IGF-II protein staining was seen in tumor epithelium in only three cases. The results of our study demonstrate that, in breast cancer, IGF-II mRNA is expressed in the smooth muscle and stromal components in the majority of invasive breast cancers. IGF-II expression correlates positively with the amount of stromal tissue present within a tumor. This suggests that IGF-II may have an important growth regulatory effect on breast tumor epithelium through paracrine pathways.

Key words

IGF-II breast cancer immunohistochemistry in situ hybridization 

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References

  1. 1.
    Lippman ME, Dickson RB, Gelmann EP, Rosen N, Knabbe C, Bates S, Bronzert D, Huff K, Kasid A: Growth regulation of human breast carcinoma occurs through regulated growth factor secretion. J Cell Biochem 35: 1–16, 1987PubMedGoogle Scholar
  2. 2.
    Osborne CK, Coronado EB, Kitten LJ, Arteaga CI, Fuqua SAW, 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 IGF-I receptor. Mol Endocrinol 3: 1701–1709, 1989PubMedGoogle Scholar
  3. 3.
    Dickson RB, Lippman ME: Mechanism of growth control in normal and malignant breast epithelium. Recent Prog Horm Res 45: 383–485, 1989PubMedGoogle Scholar
  4. 4.
    Humbel RE: Insulin-like growth factors I and II. Eur J Biochem 190: 445–462, 1990PubMedGoogle Scholar
  5. 5.
    Cullen KJ, Allison A, Martire I, Ellis M, Singer C: Insulin-like growth factor expression in breast cancer epithelium and stroma. Breast Cancer Res Treat 22: 21–29, 1992PubMedGoogle Scholar
  6. 6.
    Furlanetto RW, Dicarlo JN: Somatomedin-C receptors and growth effects in human breast cells maintained in longterm tissue culture. Cancer Res 48: 2122–2128, 1984Google Scholar
  7. 7.
    Myal Y, Shiu RPC: Receptor-binding and growth-promoting activity of insulin-like growth factors in human breast cancer cells (T-47D) in culture. Cancer Res 44: 5486–5490, 1984PubMedGoogle Scholar
  8. 8.
    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, 1988PubMedGoogle Scholar
  9. 9.
    Karey KP, Sirbasku DA: Differential responsiveness of human breast cancer cell lines MCF-7 and T47D to growth factors and 17beta-estradiol. Cancer Res 48: 4083–4092, 1988PubMedGoogle Scholar
  10. 10.
    Yee D, Paik S, Gail S, Lebovic SL, Marcus RR, Favoni RE, Cullen KJ, Lippman ME, Rosen N: Analysis of insulin-like growth factor I gene expression in malignancy: evidence of paracrine role in human breast cancer. Mol Endocrinol 3: 509–517, 1989PubMedGoogle Scholar
  11. 11.
    Paik S: Expression of IGF-I and IGF-II in breast tissue. Breast Cancer Res Treat 22: 31–38, 1992PubMedGoogle Scholar
  12. 12.
    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: 4978–4985, 1991PubMedGoogle Scholar
  13. 13.
    Bondy C: Mapping of brain insulin-like growth factor receptor gene expression byin situ hybridization. Neuroprotocols 1: 240–249, 1992Google Scholar
  14. 14.
    Yang DY, Rogler CE: Analysis of insulin-like growth factor II expression in neoplastic nodules and hepatocellular carcinomas of woodchucks utilizingin situ hybridization and immunocytochemistry. Carcinogenesis 12: 1893–1901, 1991PubMedGoogle Scholar
  15. 15.
    Giani C, Campani D, De Negri F, Capotorti E, Savarese M, Benigni G, Incensati R, Breccia M, Miccoli P, Evangelista G, Squartini F, Pinchera A: Relationship between progesterone receptor, axillary node status and productive fibrosis in ductal infiltrating carcinoma of the breast. Appl Pathol 7: 225–232, 1989PubMedGoogle Scholar
  16. 16.
    Adams EF, Newton CJ, Braunsberg H, Shaikh N, Ghilchic M, James VH: Effects of human breast fibroblasts on growth and 17beta estradiol dehydrogenase activity of MCF-7 in culture. Breast Cancer Res Treat 11: 162–172, 1988Google Scholar
  17. 17.
    Camps JL, Chang SM, Hsu TC, Freeman MR, Hong SJ, Zhau HE, Von Eschenbach AC, Chung LWK: Proc Natl Acad Sci USA 87: 75–79, 1990Google Scholar
  18. 18.
    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, 1987Google Scholar
  19. 19.
    De Chiara TM, Efstratiadis A, Robertson EJ: A growth-deficiency phenotype in heterozygous mice carrying an insulin-like growth factor II gene disrupted by targeting. Nature 345: 78–80, 1990PubMedGoogle Scholar
  20. 20.
    Nelson CF: The molecular and cellular biology of insulinlike growth factor II. Prog in Growth Factor Res 4: 257–290, 1992Google Scholar
  21. 21.
    Colletta AA, Wakefield LM, Howell FV, van Roozendaal KEP, Danielpour D, Ebbs SR, Sporn MB, Baum M: Antioestrogens induce the secretion of active transforming growth factor beta from human fetal fibroblasts. Br J Cancer 62: 405–409, 1990PubMedGoogle Scholar
  22. 22.
    Schor Sl, Schor AM, Durning P, Rushton G: Skin fibroblasts obtained from cancer patients display fetal-like migratory behavior on collagen gels. J Cell Sci 73: 235–244, 1985PubMedGoogle Scholar
  23. 23.
    Pfeffer L, Lipkin M, Stutman O, Kopelovich L: Growth abnormalities of cultured human skin fibroblasts derived from individual with hereditary adenomatosis of colon and rectum. J Cell Physiol 89: 29–37, 1976PubMedGoogle Scholar
  24. 24.
    Azzarone B, Mareel M, Billard C, Scemana P, Chaponnier C, Maciera-Coelho A: Abnormal properties of skin fibroblasts from patients with breast cancer. Int J Cancer 33: 759–764, 1984PubMedGoogle Scholar
  25. 25.
    Azzarone B, Maciera-Coelho A: Further characterization of the defects of skin fibroblasts from cancer patients. J Cell Sci 87: 155–162Google Scholar
  26. 26.
    Sappino AP, Skalli O, Jackson B, Schurch W, Gabbiani G: Smooth muscle differentiation in stromal cells of malignant and non-malignant breast tissue. Int J Cancer 41: 707–712, 1988PubMedGoogle Scholar
  27. 27.
    Yee D, Cullen KJ, Paik S, Perdue JF, Lippman ME, Rosen N: Insulin-like growth factor expression in human breast cancer. Cancer Res 48: 6691–6696, 1988PubMedGoogle Scholar
  28. 28.
    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: 91–100, 1992PubMedGoogle Scholar

Copyright information

© Kluwer Academic Publishers 1996

Authors and Affiliations

  • Claudio Giani
    • 1
  • Kevin J. Cullen
    • 3
  • Daniela Campani
    • 2
  • Audrey Rasmussen
    • 3
  1. 1.Institute of EndocrinologyUniversity of PisaPisaItaly
  2. 2.Institute of PathologyUniversity of PisaPisaItaly
  3. 3.Vincent T. Lombardi Cancer Research CenterGeorgetown University Medical CenterWashington, DCUSA

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