Abstract
Most breast cancer patients treated with anti-oestrogens will eventually develop resistance towards treatment. Therefore it is important to find new therapeutic agents effective for treatment of patients relapsing on anti-oestrogen. The vitamin D analogue EB1089 (Seocalcitol TM) is a promising new agent for treatment of breast cancer patients with advanced disease, and in this study we show that two different anti-oestrogen-resistant human breast cancer cell lines are more sensitive towards treatment with EB1089, than the parent MCF-7 cell line. The two resistant cell lines both express a lower content of the anti-apoptotic protein Bcl-2, and we suggest that this may explain the higher sensitivity towards EB1089. The importance of Bcl-2 for response to EB1089 is supported by our observation that oestradiol abrogates the effect of EB1089 in cell lines which increase Bcl-2 in response to oestradiol treatment. Overall these results indicate that treatment with SeocalcitolTMmay prove effective when patients become refractory to anti-oestrogen therapy, and that Bcl-2 may be used as a predictive marker. © 2001 Cancer Research Campaign
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References
Brünner N, Boysen B, Jirus S, Skaar TC, Holst HC, Lippman J, Frandsen T, Spang Thomsen M, Fuqua SW and Clarke R (1997) MCF7/LCC9: An antiestrogen-resistant MCF-7 variant in which acquired resistance to the steroidal antiestrogen ICI 182,780 confers an early cross-resistance to the nonsteroidal antiestrogen tamoxifen. Cancer Res 57: 3486–3493
Colston KW, Perks CM, Xie SP and Holly JM (1998) Growth inhibition of both MCF-7 and Hs578T human breast cancer cell lines by vitamin D analogues is associated with increased expression of insulin-like growth factor binding protein-3. J Mol Endocrinol 20: 157–162
Dong LA, Wang WL, Wang F, Stoner M, Reed JC, Harigai M, Samudio I, Kladde MP, Vyhlidal C and Safe S (1999) Mechanisms of transcriptional activation of bcl-2 gene expression by 17 beta-oestradiol in breast cancer cells. J Biol Chem 274: 32099–32107
El Abdaimi K, Papavasiliou V, Rabbani SA, Rhim JS, Goltzman D and Kremer R (1999) Reversal of hypercalcemia with the vitamin D analogue EB1089 in a human model of squamous cancer. Cancer Res 59: 3325–3328
Elledge RM, Green S, Howes L, Clark GM, Berardo M, Allred DC, Pugh R, Ciocca D, Ravdin P, O’Sullivan J, Rivkin S, Martino S and Osborne CK (1997) bcl-2, p53, and response to tamoxifen in estrogen receptor-positive metastatic breast cancer: a Southwest Oncology Group study. J Clin Oncol 15: 1916–1922
Gee JM, Robertson JF, Ellis IO, Willsher P, McClelland RA, Hoyle HB, Kyme SR, Finlay P, Blamey RW and Nicholson RI (1994) Immunocytochemical localization of BCL-2 protein in human breast cancers and its relationship to a series of prognostic markers and response to endocrine therapy. Int J Cancer 59: 619–628
Gulliford T, English J, Colston KW, Menday P, Moller S and Coombes RC (1998) A phase I study of the vitamin D analogue EB 1089 in patients with advanced breast and colorectal cancer. Br J Cancer 78: 6–13
Hansen CM, Hamberg KJ, Binderup E and Binderup L (2000) 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
Holmqvist P, Lundstrom M and Stal O (1999) Apoptosis and Bcl-2 expression in relation to age, tumor characteristics and prognosis in breast cancer. South-East Sweden Breast Cancer Group. Int J Biol Markers 14: 84–91
Howell A, Dodwell DJ, Laidlaw I, Anderson H and Anderson E (1990) Tamoxifen as an agonist for metastatic breast cancer. In: Endocrine Therapy of Breast Cancer IV, Veronesi (ed), pp 49–58, Springer Verlag: Berlin
Howell A, Defriend D, Robertson J, Blamey R and Walton P (1995) Response to a specific antioestrogen (ICI 182780) in tamoxifen-resistant breast cancer. Lancet, 29–30
Huynh H, Yang X and Pollak M (1996a) Estradiol and antiestrogens regulate a growth inhibitory insulin-like growth factor binding protein 3 autocrine loop in human breast cancer cells. J Biol Chem 271: 1016–1021
Huynh H, Yang XF and Pollak M (1996b) A role for insulin-like growth factor binding protein 5 in the antiproliferative action of the antiestrogen ICI 182780. Cell Growth Differ 7: 1501–1506
James SY, Mercer E, Brady M, Binderup L and Colston KW (1998a) EB1089, a synthetic analogue of vitamin D, induces apoptosis in breast cancer cells in vivo and in vitro. Br J Pharmacol 125: 953–962
Jensen BL, Skouv J, Lundholt BK and Lykkesfeldt AE (1999) Differential regulation of specific genes in MCF-7 and the ICI 182780-resistant cell line MCF-7/182R-6. Br J Cancer 79: 386–392
Keen JC, Dixon JM, Miller EP, Cameron DA, Chetty U, Hanby A, Bellamy C and Miller WR (1997) The expression of Ki-Sl and BCL-2 and the response to primary tamoxifen therapy in elderly patients with breast cancer. Breast Cancer Res Treat 44: 123–133
Kobayashi S, Iwase H, Ito Y, Yamashita H, Iwata H, Yamashita T, Ito K, Toyama T, Nakamura T and Masaoka A (1997) Clinical significance of bcl-2 gene expression in human breast cancer tissues. Breast Cancer Res Treat 42: 173–181
Larsen SS, Madsen MW, Jensen BL and Lykkesfeldt AE (1997) Resistance of human breast-cancer cells to the pure steroidal anti-oestrogen ICI 182,780 is not associated with a general loss of estrogen-receptor expression or lack of estrogen responsiveness. Int J Cancer 72: 1129–1136
Larsen SS, Egeblad M, Jäätelä M and Lykkesfeldt AE (1999) Acquired antiestrogen resistance in MCF-7 human breast cancer sublines is not accomplished by altered expression of receptors in the ErbB-family. Breast Cancer Res Treat 58: 41–56
Lipponen P, Pietilainen T, Kosma VM, Aaltomaa S, Eskelinen M and Syrjanen K (1995) Apoptosis suppressing protein bcl-2 is expressed in well-differentiated breast carcinomas with favourable prognosis. J Pathol 177: 49–55
Love SC, Gibson DF, Ratnam AV and Bikle DD (1996) Antiestrogen potentiation of antiproliferative effects of vitamin D3 analogues in breast cancer cells. Cancer Res 56: 2789–2794
Lykkesfeldt AE and Briand P (1986) Indirect mechanism of oestradiol stimulation of cell proliferation of human breast cancer cell lines. Br J Cancer 53: 29–35
Lykkesfeldt AE and Sørensen EK (1992) Effect of estrogen and antiestrogens on cell proliferation and synthesis of secreted proteins in the human breast cancer cell line MCF-7 and a tamoxifen resistant variant subline, AL-1. Acta Oncol 31: 131–138
Lykkesfeldt AE, Madsen MW and Briand P (1994) Altered expression of estrogen-regulated genes in a tamoxifen-resistant and ICI 164,384 and ICI 182,780 sensitive human breast cancer cell line, MCF-7/TAMR-1. Cancer Res 54: 1587–1595
Lykkesfeldt AE, Larsen SS and Briand P (1995) Human breast cancer cell lines resistant to pure anti-estrogens are sensitive to tamoxifen treatment. Int J Cancer 61: 529–534
Madsen MW, Reiter BE, Larsen SS, Briand P and Lykkesfeldt AE (1997) 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
Mathiasen IS, Colston KW and Binderup L (1993) EB 1089, a novel vitamin D analogue, has strong antiproliferative and differentiation inducing effects on cancer cells. J Steroid Biochem Mol Biol 46: 365–371
Mathiasen IS, Lademann U and Jaattela M (1999) 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
Narvaez CJ and Welsh J (1997) Differential effects of 1,25-dihydroxyvitamin D3 and tetradecanoylphorbol acetate on cell cycle and apoptosis of MCF-7 cells and a vitamin D3-resistant variant. Endocrinology 138: 4690–4698
Nolan E, Donepudi M, Van Weelden K, Flanagan L and Welsh J (1998) Dissociation of vitamin D-3 and anti-estrogen mediated growth regulation in MCF-7 breast cancer cells. Mol Cell Biochem 188: 13–20
Olopade OI, Adeyanju MO, Safa AR, Hagos F, Mick R, Thompson CB and Recant WM (1997) Overexpression of BCL-x protein in primary breast cancer is associated with high tumor grade and nodal metastases. Cancer J Sci Am 3: 230–237
Oltvai ZN and Korsmeyer SJ (1994) Checkpoints of dueling dimers foil death wishes. Cell 79: 189–192
Osborne CK, Yochmowitz MG, Knight WA and McGuire WL (1980) The value of estrogen and progesterone receptors in the treatment of breast cancer. Cancer 46: 2884–2888
Osborne CK, Coronado HE, Hilsenbeck SG, McCue BL, Wakeling AE, McClelland RA, Manning DL and Nicholson RI (1995) Comparison of the effects of a pure steroidal antiestrogen with those of tamoxifen in a model of human breast cancer. J Natl Cancer Inst 87: 746–750
Perillo B, Sasso A, Abbondanza C and Palumbo G (2000) 17beta-Estradiol inhibits apoptosis in MCF-7 cells, inducing bcl-2 expression via two estrogen-responsive elements present in the coding sequence. Molecular and Cellular Biology 20: 2890–2901
Rozen F, Yang XF, Huynh H and Pollak M (1997) Antiproliferative action of vitamin D-related compounds and insulin-like growth factor-binding protein 5 accumulation. J Natl Cancer Inst 89: 652–656
Silvestrini R, Benini E, Veneroni S, Daidone MG, Tomasic G, Squicciarini P and Salvadori B (1996) p53 and bcl-2 expression correlates with clinical outcome in a series of node-positive breast cancer patients. J Clin Oncol 14: 1604–1610
Simboli CM, Narvaez CJ, van WK, Tenniswood M and Welsh J (1997) 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
Swami S, Krishnan AV and Feldman D (2000) 1alpha,25-Dihydroxyvitamin D3 down-regulates estrogen receptor abundance and suppresses estrogen actions in MCF-7 human breast cancer cells. Clin Cancer Res 6: 3371–3379
Welsh J (1994) Induction of apoptosis in breast cancer cells in response to vitamin D and antiestrogens. Biochem Cell Biol 72: 537–545
Welsh J (1997) Vitamin D compounds as potential therapeutics for estrogen-independent breast cancer [editorial]. Nutrition 13: 915–917
Wiseman LR, Johnson MD, Wakeling AE, Lykkesfeldt AE, May FE and Westley BR (1993) Type I IGF receptor and acquired tamoxifen resistance in oestrogen-responsive human breast cancer cells. Eur J Cancer 29A: 2256–2264
Xie SP, James SY and Colston KW (1997) Vitamin D derivatives inhibit the mitogenic effects of IGF-I on MCF-7 human breast cancer cells. J Endocrinol 154: 495–504
Xie SP, Pirianov G and Colston KW (1999) Vitamin D analogues suppress IGF-I signalling and promote apoptosis in breast cancer cells. Eur J Cancer 35: 1717–1723
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Larsen, S., Heiberg, I. & Lykkesfeldt, A. 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). https://doi.org/10.1054/bjoc.2000.1646
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DOI: https://doi.org/10.1054/bjoc.2000.1646