Abstract
Development of resistance to antihormonal therapy is a major problem in the treatment of breast cancer patients. Metastatic tumors, which progress after a period of response to treatment, often respond to second line endocrine treatment, but eventually develop estrogen independent growth. Vitamin D analogues are promising new drugs, using alternative mechanisms to inhibit growth of breast cancer cells. The sensitivity to antiestrogens and vitamin D analogues has been proposed to be inverse, indicating that the sensitivity to vitamin D analogues might increase after development of antiestrogen resistance and vice versa. In this study, the inverse sensitivity between antiestrogens and the vitamin D analogue EB1089 was examined in antiestrogen and vitamin D resistant breast cancer cell lines. The majority of the investigated antiestrogen resistant cell lines had increased sensitivity to treatment with the vitamin D analogue EB1089. In addition, growth of a vitamin D resistant cell line was more inhibited by the pure antiestrogen ICI 182,780 than the growth of the parental cells, indicating that the compounds may be used sequentially. An association between the expression level of the vitamin D receptor (VDR) and EB1089 sensitivity was observed, suggesting that VDR is a possible predictive marker for response to vitamin D treatment. Valuation of Bcl-2 gene expression may be useful in combination with VDR to predict the outcome of treatment with EB1089. Furthermore, we observed a synergistic growth inhibition and an abrogated development of resistance upon combined treatment with ICI 182,780 and EB1089. Therefore, antiestrogens and vitamin D analogues may also be used as combined treatment for breast cancer patients in the future.
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References
American Cancer Society: Cancer facts and figures, www.cancer.org, 2002
Mouridsen H, Gershanovich M, Sun Y, Perez-Carrion R, Boni C, Monnier A, Apffelstaedt J, Smith R, Sleeboom HP, Janicke F, Pluzanska A, Dank M, Becquart D, Bapsy PP, Salminen E, Snyder R, Lassus M, Verbeek JA, Staffler B, Chaudri-Ross HA, Dugan M: Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group. J Clin Oncol 19: 2596–2606, 2001
Nabholtz JM, Buzdar A, Pollak M, Harwin W, Burton G, Mangalik A, Steinberg M, Webster A, von Euler M: Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. Arimidex Study Group. J Clin Oncol 18: 3758–3767, 2000
Rose C, Thorpe SM, Andersen KW, Pedersen BV, Mouridsen HT, Blichert-Toft M, Rasmussen BB: Beneficial effect of adjuvant tamoxifen therapy in primary breast cancer patients with high oestrogen receptor values. Lancet 1: 16–19, 1985
Dowsett M, Ellis MJ: Role of biologic markers in patient selection and application to disease prevention. Am J Clin Oncol 26: S34–S39, 2003
Johnston SR, Saccani-Jotti G, Smith IE, Salter J, Newby J, Coppen M, Ebbs SR, Dowsett M: Changes in estrogen receptor, progesterone receptor, and pS2 expression in Antiestrogen and vitamin D treatment of human breast cancer cell lines 63 tamoxifen-resistant human breast cancer. Cancer Res 55: 3331–3338, 1995
MadsenMW, Reiter BE, Larsen SS, Briand P, Lykkesfeldt AE: Estrogen receptor messenger RNA splice variants are not involved in antiestrogen resistance in sublines of MCF-7 human breast cancer cells. Cancer Res 57: 585–589, 1997
Osborne CK, Yochmowitz MG, Knight III WA, McGuire WL: The value of estrogen and progesterone receptors in the treatment of breast cancer. Cancer 46: 2884–2888, 1980
Blichert-Toft M, Ejlertsen B, Mouridsen H, Overgaard M: Breast cancer. Ugeskr Laeger 164: 3023–3026, 2002
Evans TR, Colston KW, Lofts FJ, Cunningham D, Anthoney DA, Gogas H, de Bono JS, Hamberg KJ, Skov T, Mansi JL: A phase II trial of the vitamin D analogue Seocalcitol (EB1089) in patients with inoperable pancreatic cancer. Br J Cancer 86: 680–685, 2002
Hansen CM, Hamberg KJ, Binderup E, Binderup L: Seocalcitol (EB 1089): a vitamin D analogue of anti-cancer potential. Background, design, synthesis, pre-clinical and clinical evaluation. Curr Pharm Des 6: 803–828, 2000
Colston KW, Mackay AG, James SY, Binderup L, Chander S, Coombes RC: EB1089: a new vitamin D analogue that inhibits the growth of breast cancer cells in vivo and in vitro. Biochem Pharmacol 44: 2273–2280, 1992
Bower M, Colston KW, Stein RC, Hedley A, Gazet JC, Ford HT, Combes RC: Topical calcipotriol treatment in advanced breast cancer. Lancet 337: 701–702, 1991
Nolan E, Donepudi M, VanWeelden K, Flanagan L, Welsh J: Dissociation of vitamin D3 and anti-estrogen mediated growth regulation in MCF-7 breast cancer cells. Mol Cell Biochem 188: 13–20, 1998
Larsen SS, Heiberg I, Lykkesfeldt AE: Anti-oestrogen resistant human breast cancer cell lines are more sensitive towards treatment with the vitamin D analogue EB1089 than parent MCF-7 cells. Br J Cancer 84: 686–690, 2001
Hansen CM, Rohde L, Madsen MW, Hansen D, Colston KW, Pirianov G, Holm PK, Binderup L: MCF-7/VD(R): a new vitamin D resistant cell line. J Cell Biochem 82: 422–436, 2001
Jensen SS, Madsen MW, Lukas J, Bartek J, Binderup L: Sensitivity to growth suppression by 1alpha,25-dihydroxyvitamin D(3) among MCF-7 clones correlates with vitamin D receptor protein induction. J Steroid Biochem Mol Biol 81: 123–133, 2002
Mathiasen IS, Lademann U, Jaattela M: Apoptosis induced by vitamin D compounds in breast cancer cells is inhibited by Bcl-2 but does not involve known caspases or p53. Cancer Res 59: 4848–4856, 1999
Briand P, Lykkesfeldt AE: Effect of estrogen and antiestrogen on the human breast cancer cell line MCF-7 adapted to growth at low serum concentration. Cancer Res 44: 1114–1119, 1984
Lykkesfeldt AE, Briand P: Indirect mechanism of oestradiol stimulation of cell proliferation of human breast cancer cell lines. Br J Cancer 53: 29–35, 1986
Lykkesfeldt AE, Larsen SS, Briand P: Human breast cancer cell lines resistant to pure anti-estrogens are sensitive to tamoxifen treatment. Int J Cancer 61: 529–534, 1995
Lundholt BK, Briand P, Lykkesfeldt AE: Growth inhibition and growth stimulation by estradiol of estrogen receptor transfected human breast epithelial cell lines involve different pathways. Breast Cancer Res Treat 67: 199–214, 2001
Slinker BK: The statistics of synergism. JMol Cell Cardiol 30: 723–731, 1998
DeFriend DJ, Howell A, Nicholson RI, Anderson E, Dowsett M, Mansel RE, Blamey RW, Bundred NJ, Robertson JF, Saunders C: Investigation of a new pure antiestrogen (ICI 182780) in women with primary breast cancer. Cancer Res 54: 408–414, 1994
Fisher B, Fisher ER, Redmond C, Brown A: Tumor nuclear grade, estrogen receptor, and progesterone receptor: their value alone or in combination as indicators of outcome following adjuvant therapy for breast cancer. Breast Cancer Res Treat 7: 147–160, 1986
McGuire WL: Hormone receptors: their role in predicting prognosis and response to endocrine therapy. Semin Oncol 5: 428–433, 1978
Dong L, Wang W, Wang F, Stoner M, Reed JC, Harigai M, Samudio I, Kladde MP, Vyhlidal C, Safe S: Mechanisms of transcriptional activation of bcl-2 gene expression by 17beta-estradiol in breast cancer cells. J Biol Chem 274: 32099–32107, 1999
Simboli-Campbell M, Narvaez CJ, van Weelden K, Tenniswood M, Welsh J: Comparative effects of 1,25(OH)2D3 and EB1089 on cell cycle kinetics and apoptosis in MCF-7 breast cancer cells. Breast Cancer Res Treat 42: 31–41, 1997
Vink-van Wijngaarden T, Pols HA, Buurman CJ, van den Bemd GJ, Dorssers LC, Birkenhager JC, van Leeuwen JP: Inhibition of breast cancer cell growth by combined treatment with vitamin D3 analogues and tamoxifen. Cancer Res 54: 5711–5717, 1994
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Christensen, G., Jepsen, J., Fog, C. et al. Sequential Versus Combined Treatment of Human Breast Cancer Cells with Antiestrogens and the Vitamin D Analogue EB1089 and Evaluation of Predictive Markers for Vitamin D Treatment. Breast Cancer Res Treat 85, 53–63 (2004). https://doi.org/10.1023/B:BREA.0000021047.37869.95
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DOI: https://doi.org/10.1023/B:BREA.0000021047.37869.95