Abstract
Leukemia inhibitory factor (LIF) is a pleiotropic inflammatory cytokine. A potential role for LIF in the pathogenesis of human breast cancer was recently indicated by the finding that LIF is produced by MDA-MB 231 breast cancer cells and that it stimulates proliferation of the T47D and MCF-7 breast cancer cell lines. Despite its role as a possible therapeutic target in breast cancer, the transcriptional regulation of the LIF gene in breast cancer cells has not been investigated so far. In this context, we investigated the regulation of the human LIF promoter (human LIF666-luciferase) by ovarian steroids in transient transfection assays in MDA-MB 231 and T47D cells. Since the MDA-MB 231 cells are devoid of both estrogen (ER) and progesterone (PR) receptors, these cells were co-transfected with the respective receptor expression vector. Estradiol induced no stimulation in either T47D or ER-transfected MDA-MB 231 cells. Treatment with the progesterone agonist MPA (medroxy-progesterone acetate) resulted in induction of LIF transcription in PR-transfectant MDA-MB 231 cells, while it had no effect in T47D cells. Both PR isoforms (PR-B and PR-A) were effective in inducing the LIF promoter in MDA-MB 231 cells, and this effect was inhibited by the progestin antagonist RU 486. The stimulatory effect of MPA was maintained on deletion constructs (h274LIF-Luc, h148LIF-Luc and h82LIF-Luc), indicating that 82 bp are sufficient to mediate this effect. Our results indicate that the LIF promoter is transcriptionally active in human breast cancer cells and its activity can be modulated by progestins and anti-progestins in cells expressing the LIF protein, which might have therapeutic implications.
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References
Metcalf D: Leukemia inhibitory factor – a puzzling polyfunctional regulator. Growth Fact 7: 169–173, 1992
Gearing DP: The leukemia inhibitory factor and its receptor. Adv Immunol 53: 31–58, 1993
Smith AG, Heath JK, Donaldson DD, Wong GG, Moreau J, Stahl M, Rogers D: Inhibition of pluripotential embryonic stem cell differentiation by purified polypeptides. Nature 336: 688–690, 1988
Williams RL, Hilton DJ, Pease S, Willson TA, Stewart CL, Gearing DP, Wagner EF, Metcalf D, Nicola NA, Gough NM: Myeloid leukemia inhibitory factor maintains the developmental potential of embryonic stem cells. Nature 336: 684–687, 1988
Yamamori T, Fukada K, Aebersold R, Korsching S, Fann MJ, Patterson PH: The cholinergic neuronal differentiation factor from heart cells is identical to leukemia inhibitory factor. Science 246: 1412–1416, 1989
Fukada K: Purification and partial characterization of a cholinergic neuronal differentiation factor. Proc Natl Acad Sci USA 82: 8795–8799, 1985
Mori M, Yamaguchi K, Aba K: Purification of a lipoprotein lipase-inhibiting protein produced by a melanoma cell line associated with cancer cachexia. Biochem Biophys Res Commun 160: 1085–1092, 1989
Gascan H, Godard A, Ferenz C, Naulet J, Praloran V, Peyrat MA, Hewick R, Jacques Y, Moreau JF, Soulillou JP: Characterization and NH2-terminal amino acid sequence of natural human interleukin for DA cells: Leukemia inhibitory factor. Differentiation inhibitory activity secreted by a T lymphoma cell line. J Biol Chem 264: 21509–21515, 1989
Moreau JF, Donaldson DD, Bennett F, Witek GJ, Clark SC, Wong GG: Leukemia inhibitory factor is identical to the myeloid growth factor human interleukin for DA cells. Nature 336: 690–692, 1988
Baumann H, Wong GG: Hepatocyte-stimulating factor III shares structural and functional identity with leukemia-inhibitory factor. J Immunol 143: 1163–1167, 1989
Conquet F, Brulet P: Developmental expression of myeloid leukemia inhibitory factor gene in preimplantation blastocysts and in extraembryonic tissue of mouse embryos. Mol Cell Biol 10: 3801–3805, 1990
Bhatt H, Brunet LJ, Stewart CL: Uterine expression of leukemia inhibitory factor coincides with the onset of blastocyst implantation. Proc Natl Acad Sci USA 88: 11408–11412, 1991
Stewart CL, Kaspar P, Brunet LJ, Bhatt H, Gadi I, Kontgen F, Abbondanzo SJ: Blastocyst implantation depends on maternal expression of leukemia inhibitory factor. Nature 359: 76–79, 1992
Kojima K, Kanzaki H, Iwai M, Hatayama H, Fujimoto M, Inoue T, Horie K, Nakayama H, Fujita J, Mori T: Expression of leukemia inhibitory factor in human endometrium and placenta. Biol Reprod 50: 882–887, 1994
Charnock-Jones DS, Sharkey AM, Fenwick P, Smith SK: Leukemia inhibitory factor mRNA concentration peaks in human endometrium at the time of implantation and the blastocyst contains mRNA. J Reprod Fertil 101: 421–426, 1994
Chen D-B, Hilsenrath R, Yang Z-M, Le S-P, Kim S-R, Chuong CJ, Poindexter AN III, Harper MJK: Leukemia inhibitory factor in human endometrium during the menstrual cycle: cellular origin and action on production of glandular epithelial cell prostaglandin in vitro. Hum Reprod 10: 911–918, 1995
Vogiagis D, Marsh MM, Fry RC, Salamonsen LA: Leukemia inhibitory factor in human endometrium throughout the menstrual cycle. J Endocrinol 148: 95–102, 1996
Kellokumpu-Lehtinen P, Talpaz M, Harris D, Van Q, Kurzrock R, Estrov Z: Leukemia-inhibitory factor stimulates breast, kidney and prostate cancer cell proliferation by paracrine and autocrine pathways. Int J Cancer 66: 515–519, 1996
Estrov Z, Samal B, Lapushin R, Kellokumpu-Lehtinen P, Sahin AA, Kurzrock R, Talpaz M, Aggarwal BB: Leukemia inhibitory factor binds to human breast cancer cells and stimulates their proliferation. J Interferon Cytokine Res 15: 905–913, 1995
Clarke CL, Sutherland RL: Progestin regulation of cellular proliferation. Endocr Rev 11: 266–301, 1991
Bamberger AM, Erdmann I, Bamberger CM, Jenatschke S, Schulte HM: Transcriptional regulation of the human ‘leukemia inhibitory factor’ (LIF) gene: modulation by glucocorticoids and estradiol. Mol Cell Endocrinol 127: 71–79, 1997
Bamberger AM, Jenatschke S, Erdmann I, Schulte HM: Progestin-dependent stimulation of the human ‘leukemia inhibitory factor’ (LIF) promoter in SKUT-1B uterine tumor cells. J Reprod Immunol 32: 189–201, 1997
Bamberger AM, Bamberger CM, Schulte HM: Modulation of AP-1 activity by the human progesterone receptor in endometrial adenocarcinoma cells. Proc Natl Acad Sci USA 93: 6169–6174, 1996
Kastner P, Krust A, Turcotte B, Stropp U, Tora L, Gronemayer H, Chambon P: Two distinct estrogen-regulated promoters generate transcripts encoding the two functionally different human progesterone receptor forms A and B. EMBO J 9: 1603–1614, 1990
Douglas AM, Goss GA, Sutherland RL, Hilton DJ, Berndt MC, Nicola NA, Begley CG: Expression and function of members of the cytokine receptor superfamily on breast cancer cells. Oncogene 14: 661–669, 1997
Marusic A, Kalinowski JF, Jastrzebski S, Lorenzo JA: Production of leukemia inhibitory factor mRNA and protein by malignant and immortalized bone cells. J Bone Mineral Res 8: 617–624, 1993
Wetzler M, Estrov Z, Talpaz M, Kim JK, Alphonso M, Srinivasan R, Kurzrock R: Leukemia inhibitory factor in longterm adherent cultures: increased levels of bioactive protein in leukemia and modulation by IL-4, IL-1 beta, and TNF-alpha. Cancer Res 54: 1837–1842, 1994
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Bamberger, AM., Thuneke, I. & Schulte, H.M. Differential regulation of the human 'leukemia inhibitory factor' (LIF) promoter in T47D and MDA-MB 231 breast cancer cells. Breast Cancer Res Treat 47, 153–161 (1998). https://doi.org/10.1023/A:1005961403898
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DOI: https://doi.org/10.1023/A:1005961403898