Abstract
Women with estrogen receptor (ER) positive breast cancers frequently respond initially to inhibition of estrogen action but later relapse with re-growth of tumor. Previously, we have utilized MCF-7 human breast cancer cells deprived of estradiol long term (LTED cells) as the model system to study the regrowth phenomenon and have demonstrated that these cells exhibited increased cell proliferation rate and increased ER functionality during the adaptive processes. In this report, we examined the hypothesis that the mitogen-activated protein kinase (MAP kinase) signal was involved. We found that activated MAP kinase was elevated in LTED cells and that the MAP kinase specific inhibitor PD98059 was able to inhibit the elevated MAP kinase and [3H]thymidine uptake in LTED cells, suggesting mediation of DNA synthesis and proliferation by the MAP kinase pathway. Other MAP kinase upstream inhibitors, including genestein, RG13022, and mevastatin were also able to inhibit the [3H]thymidine uptake in LTED cells. Interestingly, the antiestrogen, ICI 182,780 was able to block the activated MAP kinase in LTED cells. Treatment with PD98059 did not block elevated basal ERE-CAT activity while at the same time inhibiting [3H]thymidine uptake in LTED cells. Furthermore, treatment with PD98059 partially blocked the E2-stimulated ERE-CAT activity and [3H]thymidine uptake in both LTED and in wild type cells, indicating that both MAP kinase-dependent and MAP kinase-independent pathways are involved in the transactivation function of ER. Taken together, our data suggest that the MAP kinase pathway is, in part, involved in the adaptive process which results in enhanced DNA synthesis and cell proliferation in the absence of exogenous estrogen in LTED 3ptcells.
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References
Santen RJ, Manni A, Harvey H, Redmond C: Endocrine treatment of breast cancer in women. Endocr Rev 11: 221–265, 1990
Santen RJ, Harvey HA: Use of aromatase inhibitors in breast carcinoma. Endocrine Related Cancer 6: 75–92, 1999
Masamura S, Santner SJ, Heitjan DF, Santen RJ: Estrogen derpivation causes estradiol hypersensitivity in human breast cancer cells. J Clin Endocrin Metabolism 80: 2918–2925, 1995
Howell A: Antiestrogens: future propspects. Oncology 11: 59–64, 1997
Herman ME, Katzenellenbogen BS: Alternations in transforming growth factor-a and-b production and cell responsiveness during the progression of MCF-7 human breast cancer cells to estrogen-autonomous growth. Cancer Res 54: 5867–5874, 1994
Coutts AS, Murphy LC: Elevated mitogen-activated protein kinase activity in estrogen-nonresponsive human breast cancer cells. Cancer Res 58: 4071–4074, 1998
Katzenellenbogen BS, Kendra KL, Norman MJ, Berthois Y: Proliferation, hormone 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
Daly RJ, Darbre PD: Cellular and molecular events in loss of estrogen sensitivity in ZR-75-1 and T-47-D human breast cancer cells. Cancer Res 50: 5868–5875, 1990
Welshons WV, Jordan VC: Adaption of oestrogen-dependent MCF-7 cells to low oestrogen (phenol red-free) culture. Euro J Cancer Clin Oncol 23: 1935–1939, 1987
Jeng M-H, Shupnik MA, Bender TP, Westin EH, Bandyopadhyay D, Kumar R, Masamura S, Santen RJ: Estrogen receptor expression and function in long-term estrogen-deprived human breast cancer cells. Endocrinology 139: 4164–4174, 1998
Shim WS, Conaway M, Masamura S, Yue W, Wang JP, Kmar R, Santen RJ: Estradiol hypersensitivity and mitogen-activated protein kinase expression in long-term estrogen deprived human breast cancer cells in vivo. Endocrinology 141: 396–405, 2000
Blumer KJ, Johnson GL: Diversity in function and regulation of MAP kinase pathways. Trends Biochem Sci 19: 236–240, 1994
Lange-Carter CA, Pleiman CM, Gardner AM, Blumer KJ, Johnson GL: A divergence in the MAP kinase regulatory network defined by MEK kinase and Raf. Science 260: 315–319, 1993
Davis RJ: Transcriptional regulation by MAP kinases. Mol Reprod Dev 42: 459–467, 1995
Davis RJ: The mitogen-activated protein kinase signal transduction pathway. J Biol Chem 268: 14553–14556, 1993
Bunone G, Briand PA, Miksicek RJ, Picard D: Activation of the unliganded estrogen receptor by EGF involves the MAP kinase pathway and direct phosphorylation. EMBO J 15: 2174–2183, 1996
Kato S, Endoh H, Masuhiro Y, Kitamoto T, Uchiyama S, Sasaki H, Masushige S, Gotoh Y, Nishida E, Kawashima H et al.: Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase. Science 270: 1491–1494, 1995
Leone G, Degregori J, Sears R, Jakoi L, Nevins JR: Myc and Ras collaborate in inducing accumulation of active cyclin E/cdk2 and E2F. Nature 387: 422–425, 1997
Dubik D, Shiu RP:Mechanism of estrogen activation of c-myc oncogene expression. Oncogene 7: 1587, 1992
Ignar-Trowbridge DM, Pimentel M, Parker MG, McLachlan JA, Korach KS: Peptide growth factor cross-talk with the estrogen receptor requires the A/B domain and occurs independently of protein kinase C or estradiol. Endocrinology 137: 1735–1744, 1996
Ignar-Trowbridge DM, Nelson KG, Bidwell MC, Curtis SW, Washburn TF, Machlachlan JA, Korach KS: Coupling of dual signaling pathways: epidermal growth factor action involves the estrogen receptor. Proc Natl Acad Sci USA 89: 4658–4662, 1992
Tsai M-J, O'Malley BW: Molecular mechanisms of action of steroid/thyroid receptor superfamily members. Ann Rev Biochem 63: 451–486, 1994
Aronica SM, Katzenellenbogen BS: Stimulation of estrogen receptor-mediated transcription and alteration in the phosphorylation state of the rat uterine estrogen receptor by estrogen, cyclic adenosine monophosphate, and insulin-like growth factor-1. Mol Endocrinol 7: 743–752, 1993
Seger R, Krebs EG: The MAPK signaling cascade. FASEB J 9: 726–735, 1995
Richer JK, Lange Ca, Manning NG, Owen G, Powell R, Horwitz KB: Convergence of progesterone with growth factor and cytokine signaling in breast cancer. Progesterone receptors regulate signal transducers and activators of transcription expression and activity. J Biol Chem 273: 31317–31326, 1998
Lange CA, Richer JK, Shen T, Horwitz KB: Convergence of progesterone and epidermal growth factor signaling in breast cancer. Potentiation of mitogen-activated protein kinase pathways. J Biol Chem 273: 31308–31316, 1998
Linassier C, Pierre M, Le Pecq JB, Pierre J: Mechanisms of action in NIH-3T3 cells of genistein, an inhibitor of EGF receptor tyrosine kinase activity. Biochem Pharmacol 39: 187–193, 1990
Reddy KB, Mangold GL, Tandon AK, Yoneda T, Mundy GR, Zilberstein A, Osborne CK: Inhibition of breast cancer cell growth in vitro by a tyrosine kinase inhibitor. Cancer Res 52: 3636–3641, 1992
Danesi R, McLellan CA, Myers CE: Specific labeling of isoprenylated proteins: application to study inhibitors of the posttranslational farnesylation and geranylgeranylation. Biochem Biophys Res Commun 206: 637–643, 1995
Danesi R, Figg WD, Reed E, Myers CE: Paclitaxel (taxol) inhibits protein isoprenylation and induces apoptosis in PC-3 human prostate cancer cells. Mol Pharmacol 47: 1106–1111, 1995
Marom M, Haklai R, Ben-Baruch G, Marciano D, Egozi Y, Kloog Y: Selective inhibition of Ras-dependent cell growth by farnesylthiosalisylic acid. J Biol Chem 270: 22263–22270, 1995
Alessi DR, Cuenda A, Cohen P, dudley DT, Saltiel AR: PD 098059 is a specific inhibitor of the activitation of mitogenactivated protein kinase in vitro and in vivo. J Biol Chem 270: 27489–27494, 1995
Meydan N, Grunberger T, Dadi H, Shahar M, Arpaia E, Lapidot Z, Leeder JS, Freedman M, Cohen A, Gazit A, Levitzki A, Roifman CM: Inhibition of acute lymphoblastic leukaemia by a Jak-2 inhibitor. Nature 379: 645–648, 1996
Jeng MH, Parker CJ, Jordan VC: Estrogenic potential of progestins in oral contraceptives to stimulate human breast cancer cell proliferation. Cancer Res 52: 6539–6546, 1992
Cano E, Mahadevan LC: Parallel signal processing among mammalian MAPKs. Trends Biochem Sci 20: 117–122, 1995
Migliaccio A, Domenico MD, Castoria G, Falco Ad, Bontempo P, Nola E, Auricchio F: Tyrosine kinase/p21ras/MAPkinase pathway activation by estradiol-receptor complex in MCF-7 cells. EMBO J 15: 1292–1300, 1996
Bonapace IM, Addeo R, Altucci L, Cicatiello L, Bifulco M, Laezza C, Salzano S, Sica V, Bresciani F, Weisz A: 17 beta-Estradiol overcomes a G1 block induced by HMG-CoA reductase inhibitors and fosters cell cycle progression without inducing ERK-1 and 2-MAP kinases activation. Oncogene 12: 753–763, 1996
Joel PB, Traish AM, Lannigan DA: Estradiol-induced phosphorylation of serine 118 in the estrogen receptor is independent of p42/p44 mitogen-activated protein kinase. J Biol Chem 273: 13317–13323, 1998
Levenson AS, Jordan VC: MCF-7: The first hormoneresponsive breast cancer cell line. Cancer Res 1997: 3071–3078, 1997
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Jeng, MH., Yue, W., Eischeid, A. et al. Role of MAP kinase in the enhanced cell proliferation of long term estrogen deprived human breast cancer cells. Breast Cancer Res Treat 62, 167–175 (2000). https://doi.org/10.1023/A:1006406030612
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DOI: https://doi.org/10.1023/A:1006406030612