Abstract
The antiestrogen tamoxifen competes with estrogen for receptor occupancy, although reports indicate that not all effects of tamoxifen are mediated via this specific interaction. In the present study we sought to determine whether tamoxifen can initiate transmembrane lipid signals. Lipid signaling is a prominent mode by which hormones, growth factors, and phorbol diesters transduce messages. Using the human mammary carcinoma cell line MDA-MB-231, phospholipid metabolism was analyzed in cells prelabeled with3H-fatty acid. After short-term (10 min) exposure to tamoxifen (10 µM), cellular phosphatidic acid (PA) increased by approximately 50%. Dose-response kinetics for PA formation were obtained over a tamoxifen range of 2.5-20 µM. Treatment of MDA-MB-231 cells with phorbol diester (12-O-tetradecanoylphorbol-13-acetate, TPA) also elicited PA generation (60% above control). Interestingly, addition of tamoxifen, a purported protein kinase C inhibitor, to TPA-treated cells, caused further increase in PA (approximately 100% above control). PA, a second messenger lipid produced upon effector-receptor coupling, shares a prominent role in signal transduction events that govern cellular proliferation. It is therefore suggested that some actions of tamoxifen are mediated by promoting production of second messenger lipids that elicit transmembrane signal transduction cascades. This view is in line with ideas on non-estrogen receptor associated actions of tamoxifen by way of alternate binding sites.
References
Marshall E: Tamoxifen: Hanging in the balance. Science (Washington D.C.) 264: 1524–1527, 1994
Issandou M, Faucher C, Bayard F, Darbon JM: Opposite effects of tamoxifen onin vitro protein kinase C activity and endogeneous protein phosphorylation in intact MCF-7 cells. Cancer Res 50: 5845–5850, 1990
Butta A, MacLennan K, Flanders KC, Sacks PM, Smith I, McKinna A, Dowsett M, Wakefield LM, Sporn MB, Baum M, Colletta AA: Induction of transforming growth factor β1 in human breast cancerin vivo following tamoxifen treatment. Cancer Res 52: 4261–4264, 1992
Horgan K, Cooke E, Hallett MB, Mansel RE: Inhibition of protein kinase C mediated signal transduction by tamoxifen. Biochem Pharmacol 24: 4463–4465, 1986
O'Brien CA, Liskamp RM, Solomon DH, Weinstein IB: Inhibition of protein kinase C by tamoxifen. Cancer Res 45:2462–2465, 1985
Katzenellenbogen BS, Kendra KL, Norman MJ, Berthois Y: Proliferation, hormonal responsiveness, and estrogen receptor content of MCF-7 human breast cancer cells grown in the short-term and long-term absence of estrogens. Cancer Res 47: 4355–4360, 1987
Wakeling AE, Newboult E, Peters SW: Effects of antiestrogens on the proliferation of MCF-7 human breast cancer cells. J Molec Endocrinol 2: 225–234, 1989
Tormey DC, Simon RM, Lippman ME, Bull JM, Meyer CE: Evaluation of tamoxifen dose in advanced breast cancer: a progress report. Cancer Treat Rep 60: 1451–1459, 1976
Plotkin D, Lechner JJ, Jung WE, Risen PJ: Tamoxifen flare in advanced breast cancer. JAMA 240: 2644–2646, 1978
Gottardis MM, Jiang SY, Jeng MH, Jordan VC: Inhibition of tamoxifen-stimulated growth of an MCF-7 tumor variant in athymic mice by novel steroidal antiestrogens. Cancer Res 49: 4090–4093, 1989
Reddel RR, Murphy LC, Sutherland RL: Effects of biologically active metabolites of tamoxifen on the proliferation kinetics of MCF-7 human breast cancer cellsin vitro. Cancer Res 43: 4618–4624, 1983
Sutherland RL, Hall RE, Taylor IW: Cell proliferation kinetics of MCF-7 human mammary carcinoma cells in culture and effects of tamoxifen on exponentially growing and plateau phase cells. Cancer Res 43: 3998–4006, 1983
Lerner LJ, Jordan VC: Development of antiestrogens and their use in breast cancer: eighth Cain memorial award lecture. Cancer Res 50: 4177–4189, 1990
Sutherland RL, Murphy LC, Foo MS, Green MD, Wybourne AM, Krozowski ZS: High affinity antioestrogen binding site distinct from the oestrogen receptor. Nature Lond 288: 273–275, 1980
Sudo K, Monsma FJ, Katzenellenbogen BS: Antiestrogen binding sites distinct from the estrogen receptor: subcellular localization ligand specificity and distribution in tissues of the rat. Endocrinology 112: 425–434, 1983
Watts CKW, Murphy LC, Sutherland RL: Microsomal binding sites for nonsteroidal anti-estrogens in MCF-7 human mammary carcinoma cells. J Biol Chem 259: 4223–4229, 1984
Cabot MC, McKeehan WL (eds): Mechanisms of Signal Transduction by Hormones and Growth Factors. Progress in Clinical and Biological Research 249. New York: Alan R Liss Inc, 1987
Asaoka Y, Nakamura SI, Yoshida K, Nishizuka Y: Protein kinase C, calcium and phospholipid degradation. TIBS 17: 414–418, 1992
Farooqui AA, Farooqui T, Yates AJ, Horrocks LA: Regulation of protein kinase C activity by various lipids. Neurochem Res 6: 449–511, 1988
Moolenaar WH, Kruijer W, Tilly BC, Verlaan I, Bierman AJ, de Laat SW: Growth factor-like action of phosphatidic acid. Nature (Lond) 323: 171–173, 1986
van Corven EJ, Groenink A, Jalink K, Eichholtz T, Moolenaar WH: Lysophosphatidate-induced cell proliferation: identification and dissection of signaling pathways mediated by G proteins. Cell 59: 45–54, 1989
Fukami K, Takenawa T: Phosphatidic acid that accumulates in platelet-derived growth factor stimulated Balb/c 3T3 cells is a potential mitogenic signal. J Biol Chem 267: 10988–10993, 1992
Bligh EG, Dyer WT: A rapid method of total lipid extraction and purification. Can J Biochem Physiol 37: 911–917, 1959
Huang C, Cabot MC: Phorbol diesters stimulate the accumulation of phosphatidate, phosphatidylethanol, and diacylglycerol in three cell types. J Biol Chem 265: 14858–14863, 1990
Huang C, Cabot MC: Vasopressin-induced polyphosphoinositide and phosphatidylcholine degradation in fibroblasts. J Biol Chem 265: 17468–17473, 1990
Cabot MC, Welsh CJ, Zhang ZC, Cao HT: Evidence for a protein kinase C-directed mechanism in the phorbol diester-induced phospholipase D pathway of diacylglycerol generation from phosphatidylcholine. FEBS Lett 245: 85–90, 1989
Huynh H, Pollak M: Uterotrophic actions of estradiol and tamoxifen are associated with inhibition of uterine insulinlike growth factor binding protein 3 gene expression. Cancer Res 54: 3115–3119, 1994
Cailleau R, Young R, Olive M, Reeves WJ Jr: Breast tumor cell lines from pleural effusions. J Natl Cancer Inst 53: 661–674, 1974
Exton JH: Signaling through phosphatidylcholine breakdown. J Biol Chem 265: 1–4, 1990
Daniel LW, Huang C, Strum JC, Smitherman PK, Greene D, Wykle RL: Phospholipase D hydrolysis of choline phosphoglycerides is selective for the alkyl-linked subclass of Madin-Darby canine kidney cells. J Biol Chem 268: 21519–21526, 1993
Rice GC, Brown PA, Nelson RJ, Bianco JA, Singer JW, Bursten S: Protection from endotoxic shock in mice by pharmacologic inhibition of phosphatidic acid. Proc Natl Acad Sci USA 91: 3857–3861, 1994
Bignon E, Pons M, Doré JC, Gilbert J, Ojasoo T, Miquel JF, Raynaud JP, De Paulet AC: Influence of di- and tri-phenylethylene estrogen/antiestrogen structure on the mechanisms of protein kinase C inhibition and activation as revealed by a multivariate analysis. Biochem Pharmacol 42: 1373–1383, 1991
Wiseman H: Tamoxifen: New membrane-mediated mechanisms of action and therapeutic advances. TIPS 15: 83–89, 1994
Gross C, Yu M, Van Herle AJ, Giuliano AE, Juillard JF: Presence of a specific antiestrogen binding site on human follicular thyroid carcinoma cell line (UCLA RO 82 W-1): Inhibition by an endogenous ligand present in human serum. J Clin Endocrinol Metab 77: 1361–1366, 1993
McClay EF, Albright KD, Jones JA, Christen RD, Howell SB: Tamoxifen modulation of cisplatin sensitivity of human malignant melanoma cells. Cancer Res 53: 1571–1576, 1993
Cabot MC: Cancer cells display attenuated signaling via the phosphatidylcholine pathway. In: Lipid Mediators in Health and Disease. Freund Publishing House, Ltd., London, in press
Sipila PE, Wiebe VJ, Hubbard GB, Koester SK, Emshoff VD, Maenpaa JU, Wurz GT, Seymour RC, DeGregorio MW: Prolonged tamoxifen exposure selects a breast cancer cell clone that is stablein vitro andin vivo. Eur J Cancer 29A: 2138–2144, 1993
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Cabot, M.C., Zhang, ZC. & Giuliano, A.E. Tamoxifen elicits rapid transmembrane lipid signal responses in human breast cancer cells. Breast Cancer Res Tr 36, 299–306 (1995). https://doi.org/10.1007/BF00713401
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DOI: https://doi.org/10.1007/BF00713401