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Differential regulation of normal and tumoral breast epithelial cell growth by fibroblasts and 1,25‐dihydroxyvitamin D3

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Abstract

Mesenchymal‐epithelial interactions are of paramount importance during normal and tumoral breast developments. We have investigated the paracrine growth regulation of normal and tumoral breast epithelial cells by fibroblasts derived from normal or pathological breast tissues. In some cases, breast cancer MCF‐7 cells or normal epithelial cells in primary culture were cocultured with fibroblasts in a Transwell system allowing diffusible factor exchanges. Alternatively, conditioned medium produced by fibroblast cultures was added to epithelial cell cultures. Fibroblasts were shown to stimulate the proliferation of normal and carcinoma cells through paracrine mechanisms. However, the paracrine exchanges appeared to be different in normal versus tumoral breast epithelial cell growth regulation. Moreover, vitamin D‐related compounds that have been proposed as anti‐tumoral drugs were studied for their ability to affect normal and tumoral mammary epithelial cell proliferation and to interfere with the growth‐regulatory activity of fibroblasts. Whereas vitamin D compounds inhibited MCF‐7 cell growth, they led to a marked stimulation of the proliferation of normal mammary epithelial cells. Moreover, it was shown that the vitamin D analog EB 1089 can block the mitogenic effect of fibroblast‐conditioned medium on tumoral but not normal breast epithelial cells. The differential effects of vitamin D compounds on cell proliferation provide further data in favor of the different behaviours of normal and tumoral mammary epithelial cells. The potential therapeutic use of vitamin D derivatives in the treatment of breast cancer is supported by these results but their growth‐stimulatory properties on normal epithelial cells cannot be overlooked.

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References

  1. van den Hooff A: Stromal involvement in malignant growth. Adv Cancer Res 50: 159–196, 1988

    Google Scholar 

  2. Clarke R, Dickson RB, Lippman ME: Hormonal aspects of breast cancer: Growth factors, drugs and stromal interactions. Crit Rev Oncol Hematol 12: 1–23, 1992

    Google Scholar 

  3. Enami J, Enami S, Koga M: Growth of normal and neoplastic mouse mammary epithelial cells in primary culture: Stimulation by conditioned medium from mouse mammary fibroblasts. Gann 74: 845–853, 1983

    Google Scholar 

  4. McGraph CM: Augmentation of the response of normal mammary epithelial cells to estradiol by mammary stroma. Cancer Res 43: 1355–1360, 1983

    Google Scholar 

  5. Haslam SZ: Mammary fibroblast influence on normal mouse mammary epithelial cell responses to estrogen in vitro. Cancer Res 46: 310–316, 1986

    Google Scholar 

  6. Gache C, Berthois Y, Martin PM, Saez S: Positive regulation of normal and tumoral mammary epithelial cell proliferation by fibroblasts in coculture. In Vitro Cell Dev Biol 34: 347–351, 1998

    Google Scholar 

  7. Mukaida H, Hirabayashi N, Hirai T, Iwata T, Saeki S, Toge T: Significance of freshly cultured fibroblasts from different tissues in promoting cancer cell growth. Int J Cancer 48: 423–427, 1991

    Google Scholar 

  8. Orr DJA, Ryan MC, Horgan K: Demonstration of a positive feedback loop of paracrine growth stimulation in a new coculture model of breast cancer. Breast 2: 138–143, 1993

    Google Scholar 

  9. Brouty-Boyé D, Mainguene C, Magnien V, Israel L, Beaupain R: Fibroblast-mediated differentiation in human breast carcinoma cells (MCF-7) grown as nodules in vitro. Int J Cancer 56: 731–735, 1994

    Google Scholar 

  10. Adam L, Crépin M, Lelong JC, Spanakis E, Israel L: Selective interactions between mammary epithelial cells and fibroblasts in co-cultures. Int J Cancer 59: 262–268, 1994

    Google Scholar 

  11. Hofland LJ, van der Burg B, van Eijck CHJ, Sprij DM, van Koetsveld PM, Lamberts SWJ: Role of tumor derived fibroblasts in the growth of primary cultures of human breast-cancer cells: Effects of epidermal growth factor and the somatostatin analogue octreotide. Int J Cancer 60: 93–99, 1995

    Google Scholar 

  12. Lefebvre MF, Guillot C, Crépin M, Saez S: Influence of tumor derived fibroblasts and 1,25-dihydroxyvitamin D3 on growth of breast cancer cell lines. Breast Cancer Res Treat 33: 189–197, 1995

    Google Scholar 

  13. Liu J, Bagheri-Yarmand R, Xia Y, Crépin M: Modulations of breast fibroblast and carcinoma cell interactions by a dextran derivative (CMDB7). Anticancer Res 17: 253–258, 1997

    Google Scholar 

  14. Adams EF, Newton CJ, Braunsberg H, Shaikh N, Ghilchik M, James VHT: Effects of human breast fibroblasts on growth and 17 b-estradiol dehydrogenase activity of MCF-7 cells in culture. Breast Cancer Res Treat 11: 165–172, 1988

    Google Scholar 

  15. Ryan MC, Orr DJA, Horgan K: Fibroblast stimulation of breast cancer cell growth in a serum-free system. Br J Cancer 67: 1268–1273, 1993

    Google Scholar 

  16. van Roozendaal CEP, Klijn JGM, van Ooijen B, Classen C, Eggermont AMM, Hensen-Logmans SC, Foekens JA: Differential regulation of breast tumor cell proliferation by stromal fibroblasts of various breast tissue sources. Int J Cancer 65: 120–125, 1996

    Google Scholar 

  17. Cunha GR: Role of mesenchymal-epithelial interactions in normal and abnormal development of mammary gland and prostate. Cancer 74: 1030–1044, 1994

    Google Scholar 

  18. Sakakura T: New aspects of stroma-parenchyma relations in mammary gland differentiation. Int Rev Cytol 125: 165–202, 1991

    Google Scholar 

  19. Hornby AE, Cullen KJ: Mammary tumor fibroblasts are phenotypically distinct from non-tumor fibroblasts. EXS 74: 249–272, 1995

    Google Scholar 

  20. Saez S, Meggouh F, Lefebvre MF, Descotes F, Pamphile R, Adam L, Crépin M: Potential direct and indirect influence of 1; 25.OH/2D3 on the growth of human colonic and breast carcinoma. In: Norman AW, Bouillon R, Thomasset M (eds) Vitamin D: A Pluripotent Steroid Hormone.Walter de Gruyter, Berlin, 1994, pp 469–476

    Google Scholar 

  21. Demirpence E, Balaguer P, Trousse F, Nicolas JC, Pons M, Gagne D: Antiestrogenic effects of all-trans-retinoic acid and 1,25-dihydroxyvitamin D3 in breast cancer cells occur at the estrogen response element level but through different molecular mechanisms. Cancer Res 54: 1458–1464, 1994

    Google Scholar 

  22. James SY, Mackay AG, Binderup L, Colston KW: Effects of a new synthetic vitamin D analogue, EB 1089, on the estrogenresponsive growth of human breast cancer cells. J Endocrinol 141: 555–563, 1994

    Google Scholar 

  23. Saez S, Falette N, Guillot C, Meggouh F, Lefebvre MF, Crépin M: 1; 25.OH/2D3 modulation of mammary tumor cell growth in vitro and in vivo. Breast Cancer Res Treat 33: 189–197, 1993

    Google Scholar 

  24. Vink-van Wijngaarden T, Pols HAP, Buurman CJ, Birkenhäger JC, van Leeuwen JPTM: Inhibition of insulin-and insulin-like growth factor-I-stimulated growth of human breast cancer cells by 1,25 dihydroxyvitamin D3 and the vitamin D3 analogue EB 1089. Eur J Cancer 32A: 842–848, 1996

    Google Scholar 

  25. Xie SP, James SY, Colston KW: Vitamin D derivatives inhibit the mitogenic effects of IGF-I on MCF-7 human breast cancer cells. J Endocrinol 154: 495–504, 1997

    Google Scholar 

  26. Rozen F, Yang XF, Huynh H, Pollak M: Antiproliferative action of vitamin D-related compounds and insulin-like growth factor-binding protein 5 accumulation. J Natl Cancer Inst 89: 652–656, 1997

    Google Scholar 

  27. Chouvet C, Vicard E, Devonec M, Saez S: 1,25-dihydroxyvitamin D3 inhibitory effect on the growth of two human breast cancer cell lines (MCF-7, BT-20). J Steroid Biochem 24: 373–376, 1986

    Google Scholar 

  28. Colston KW, Mackay AG, James SY, Binderup L, Chander S, Coombes RC: EB 1089: A new vitamin D analogue that inhibits the growth of breast cancer cells in vivo and in vitro. Biochem Pharmacol 15: 2273–2280, 1992

    Google Scholar 

  29. Mathiasen IS, Colston KW, Binderup L: EB 1089: A new vitamin D analogue, has strong antiproliferative and differentiation inducing effects on cancer cells. J Steroid Biochem Molec Biol 46: 365–371, 1993

    Google Scholar 

  30. Vink-van Wijngaarden T, Pols HAP, Buurman CJ, van den Bemd GJCM, Dorssers LCJ, Birkenhäger JC, van Leeuwen JPTM: Inhibition of breast cancer cell growth by combined treatment with vitamin D3 analogues and tamoxifen. Cancer Res 54: 5711–5717, 1994

    Google Scholar 

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

    Google Scholar 

  32. Ikekawa N: Structures and biological activities of vitamin D metabolites and their analogs. Med Res Rev 7: 333–366, 1987

    Google Scholar 

  33. Lissoos TW, Beno DW, Davis BH: 1,25-dihydroxyvitamin D3 activates Raf kinase and Raf perinuclear translocation via a protein kinase C-dependent pathway. J Biol Chem 268: 25132–25138, 1993

    Google Scholar 

  34. Mitsuhashi T, Morris RC Jr, Ives HE: 1,25-dihydroxyvitamin D3 modulates growth of vascular smooth muscle cells. J Clin Invest 87: 1889–1895, 1991

    Google Scholar 

  35. McLane JA, Katz M: Differential effects of 1,25-dihydroxyvitamin D3 on proliferation and biochemical differentiation of cultured human epidermal keratinocytes grown in different media. Ann N Y Acad Sci 548: 341–343, 1988

    Google Scholar 

  36. Lützow-Holm C, De Angelis P, Grosvik H, Clausen OP: 1,25-dihydroxyvitamin D3 and the vitamin D analogue KH 1060 induce hyperproliferation in normal mouse epidermis: A BrdUrd/DNA flow cytometric study. Exp Dermatol 2: 113–120, 1993

    Google Scholar 

  37. Gniadecki R, Serup J: Stimulation of epidermal proliferation in mice with 1 alpha, 25-dihydroxyvitamin D3 and receptoractive 20-epi analogues of 1 alpha, 25-dihydroxyvitamin D3. Biochem Pharmacol 49: 621–624, 1995

    Google Scholar 

  38. Buras RR, Schumaker LM, Davoodi F, Brenner RV, Shabahan M, Nauta RJ, Evans SRT: Vitamin D receptors in breast cancer cells. Breast Cancer Res Treat 31: 191–202, 1994

    Google Scholar 

  39. Gniadecki R: Activation of Raf-mitogen-activated protein kinase signaling pathway by 1,25-dihydroxyvitamin D3 in normal human keratinocytes. J Invest Dermatol 106: 1212–1217, 1996

    Google Scholar 

  40. Ellis MJC, Singer C, Hornby A, Rasmussen A, Cullen KJ: Insulin-like growth factor mediated stromal-epithelial interactions in human breast cancer. Breast Cancer Res Treat 31: 249–261, 1994

    Google Scholar 

  41. Singer C, Rasmussen A, Smith HS, Lippman ME, Lynch HT, Cullen KJ: Malignant breast epithelium selects for insulinStromal-epithelial interactions and vitamin D3 39 like growth factor II expression in breast stroma: Evidence for paracrine function. Cancer Res 55: 2448–2454, 1995

    Google Scholar 

  42. Ervin PR, Kaminski MS, Cody RL, Wicha MS: Production of mammastatin, a tissue-specific growth inhibitor, by normal human mammary cells. Science (Wash) 244: 1585–1587, 1989

    Google Scholar 

  43. Müller T, Kurtz A, Vogel F, Breter H, Schneider F, Angström U, Mieth M, Bohmer FD, Grosse R: A mammary-derived growth inhibitor (MDGI) related 70 kDa antigen identified in nuclei of mammary epithelial cells. J Cell Physiol 138: 415–423, 1989

    Google Scholar 

  44. Dong-Le Bourhis X, Berthois Y, Millot G, Degeorges A, Silvy M, Martin PM, Calvo F: Effect of stromal and epithelial cells derived from normal and tumorous breast tissue on the proliferation of human breast cancer cell lines in co-culture. Int J Cancer 71: 42–48, 1997

    Google Scholar 

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Authors and Affiliations

  1. Laboratoire des Interactions Cellulaires Intratumorales, CJF INSERM 9311, IFR Jean Roche, Facultè de Médecine secteur Nord, Bd Pierre Dramard, Marseille, France

    Cécile Gache, Yolande Berthois & Pierre‐Marie Martin

  2. Service de Chirurgie Oncologie, Centre Hospitalier Lyon Sud, Pierre Bènite, France

    Simone Saez

  3. Service d'Oncologie des Maladies Sanguines Immunitaires et Tumorales, Hopital Paul Brousse, Villejuif, France

    Esteban Cvitkovic

Authors
  1. Cécile Gache
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  2. Yolande Berthois
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  3. Esteban Cvitkovic
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  4. Pierre‐Marie Martin
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  5. Simone Saez
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Gache, C., Berthois, Y., Cvitkovic, E. et al. Differential regulation of normal and tumoral breast epithelial cell growth by fibroblasts and 1,25‐dihydroxyvitamin D3. Breast Cancer Res Treat 55, 29–39 (1999). https://doi.org/10.1023/A:1006163418479

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