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Abstract:

Interactions between steroid hormone receptors and signal transducer and activator of transcription (Stat)-mediated signaling pathways have already been described. In the present study, we explored the capacity of progestins to modulate Stat3 transcriptional activation in an experimental model of hormonal carcinogenesis in which the synthetic progestin medroxyprogesterone acetate (MPA) induced mammary adenocarcinomas in BALB/c mice and in the human breast cancer cell line T47D. We found that C4HD epithelial cells, from the MPA-induced mammary tumor model, expressed Stat3 and that MPA treatment of C4HD cells up-regulated Stat3 protein expression. In addition, MPA induced rapid, nongenomic Stat3, Jak1, and Jak2 tyrosine phosphorylation in C4HD and T47D cells. MPA treatment of C4HD cells also resulted in rapid c-Src tyrosine phosphorylation. These effects were completely abolished by the progestin antagonist RU486. Abrogation of Jak1 and Jak2 activity by transient transaction of C4HD cells with dominant negative (DN) Jak1 or DN Jak2 vectors, or inhibition of Src activity by preincubation of cells with the Src family kinase inhibitor PP2, blocked the capacity of MPA to induce Stat3 phosphorylation. Treatment of C4HD cells with MPA induced Stat3 binding to DNA. In addition, MPA promoted strong Stat3 transcriptional activation in C4HD and T47D cells that was inhibited by RU486 and by blockage of Jak1, Jak2, and Src activities. To investigate the correlation between MPA-induced Stat3 activation and cell growth, C4HD cells were transiently transfected with a DN Stat3 expression vector, Stat3Y705-F, or with a constitutively activated Stat3 mutant, Stat3-C. While expression of Stat3Y705-F mutant had an inhibitory effect on MPA-induced growth of C4HD cells, transfection with the constitutively activated Stat3-C vector resulted in MPA-independent proliferation. Finally, we addressed the effect of targeting Stat3 in in vivo growth of C4HD breast tumors. Blockage of Stat3 activation by transfection of C4HD cells with the DN Stat3Y705-F expression vector significantly inhibited these cells' ability to form tumors in syngeneic mice. Our results have for the first time demonstrated that progestins are able to induce Stat3 transcriptional activation, which is in turn an obligatory requirement for progestin stimulation of both in vitro and in vivo breast cancer growth. Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Registro:

Documento: Artículo
Título:Progestins induce transcriptional activation of signal transducer and activator of transcription 3 (Stat3) via a Jak- and Src-dependent mechanism in breast cancer cells
Autor:Proietti, C.; Salatino, M.; Rosemblit, C.; Carnevale, R.; Pecci, A.; Kornblihtt, A.R.; Molinolo, A.A.; Frahm, I.; Charreau, E.H.; Schillaci, R.; Elizalde, P.V.
Filiación:Instituto de Biología y Medicina Experimental (IBYME), CONICET, Obligado 2490, Buenos Aires, Argentina
Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
Servicio de Patología, Sanatoria Mater Dei, Buenos Aires, Argentina
Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, United States
Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología y Medicina Experimental (IBYME), Obligado 2490, Buenos Aires 1428, Argentina
Palabras clave:4 amino 7 tert butyl 5 (4 chlorophenyl)pyrazolo[3,4 d]pyrimidine; antigestagen; Janus kinase; Janus kinase 1; Janus kinase 2; medroxyprogesterone acetate; mifepristone; mutant protein; progesterone derivative; protein tyrosine kinase; STAT3 protein; steroid receptor; animal cell; animal experiment; animal model; animal tissue; article; breast adenocarcinoma; breast cancer; cancer cell; cancer model; cell growth; cell proliferation; controlled study; enzyme activity; enzyme inhibition; expression vector; female; gene induction; genetic transfection; hormonal carcinogenesis; hormonal regulation; mouse; nonhuman; oncogene src; priority journal; protein DNA binding; protein expression; protein phosphorylation; protein protein interaction; protein targeting; signal transduction; transcription initiation; tumor growth; Active Transport, Cell Nucleus; Animals; Antineoplastic Agents, Hormonal; Breast Neoplasms; Cell Line, Tumor; DNA; DNA-Binding Proteins; Epithelial Cells; Female; Humans; Janus Kinase 1; Janus Kinase 2; Medroxyprogesterone 17-Acetate; Mice; Mice, Inbred BALB C; Progestins; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Receptors, Progesterone; src-Family Kinases; STAT3 Transcription Factor; Trans-Activation (Genetics); Trans-Activators
Año:2005
Volumen:25
Número:12
Página de inicio:4826
Página de fin:4840
DOI: http://dx.doi.org/10.1128/MCB.25.12.4826-4840.2005
Título revista:Molecular and Cellular Biology
Título revista abreviado:Mol. Cell. Biol.
ISSN:02707306
CODEN:MCEBD
CAS:Janus kinase, 161384-16-3; medroxyprogesterone acetate, 71-58-9; mifepristone, 84371-65-3; protein tyrosine kinase, 80449-02-1; Antineoplastic Agents, Hormonal; DNA, 9007-49-2; DNA-Binding Proteins; JAK1 protein, human, EC 2.7.1.112; Jak1 protein, mouse; JAK2 protein, human, EC 2.7.1.112; Jak2 protein, mouse, EC 2.7.1.112; Janus Kinase 1, EC 2.7.1.112; Janus Kinase 2, EC 2.7.1.112; Medroxyprogesterone 17-Acetate, 71-58-9; Progestins; Protein-Tyrosine Kinases, EC 2.7.1.112; Proto-Oncogene Proteins; Receptors, Progesterone; src-Family Kinases, EC 2.7.1.112; STAT3 protein, human; Stat3 protein, mouse; STAT3 Transcription Factor; Trans-Activators
PDF:https://bibliotecadigital.exactas.uba.ar/download/paper/paper_02707306_v25_n12_p4826_Proietti.pdf
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_02707306_v25_n12_p4826_Proietti

Referencias:

  • Aaronson, D.S., Horvath, C.M., A road map for those who don't know JAK-STAT (2002) Science, 296, pp. 1653-1655
  • Amin, H.M., McDonnell, T.J., Ma, Y., Lin, Q., Fujio, Y., Kunisada, K., Leventaki, V., Lai, R., Selective inhibition of STAT3 induces apoptosis and G1 cell cycle arrest in ALK-positive anaplastic large cell lymphoma (2004) Oncogene, 23, pp. 5426-5434
  • Balana, M.E., Labriola, L., Salatino, M., Movsichoff, F., Peters, G., Charreau, E.H., Elizalde, P.V., Activation of ErbB-2 via a hierarchical interaction between ErbB-2 and type I insulin-like growth factor receptor in mammary tumor cells (2001) Oncogene, 20, pp. 34-47
  • Balana, M.E., Lupu, R., Labriola, L., Charreau, E.H., Elizalde, P.V., Interactions between progestins and heregulin (HRG) signaling pathways: HRG acts as mediator of progestins proliferative effects in mouse mammary adenocarcinomas (1999) Oncogene, 18, pp. 6370-6379
  • Ballare, C., Uhrig, M., Bechtold, T., Sancho, E., Di Domenico, M., Migliaccio, A., Auricchio, F., Beato, M., Two domains of the progesterone receptor interact with the estrogen receptor and are required for progesterone activation of the c-Src/Erk pathway in mammalian cells (2003) Mol. Cell. Biol., 23, pp. 1994-2008
  • Boonyaratanakornkit, V., Scott, M.P., Ribon, V., Sherman, L., Anderson, S.M., Maller, J.L., Miller, W.T., Edwards, D.P., Progesterone receptor contains a proline-rich motif that directly interacts with SH3 domains and activates c-Src family tyrosine kinases (2001) Mol. Cell, 8, pp. 269-280
  • Bowman, T., Garcia, R., Turkson, J., Jove, R., STATs in oncogenesis (2000) Oncogene, 19, pp. 2474-2488
  • Braunsberg, H., Coldham, N.G., Leake, R.E., Cowan, S.K., Wong, W., Actions of a progestogen on human breast cancer cells: Mechanisms of growth stimulation and inhibition (1987) Eur. J. Cancer Clin. Oncol., 23, pp. 563-571
  • Bromberg, J., Darnell Jr., J.E., The role of STATs in transcriptional control and their impact on cellular function (2000) Oncogene, 19, pp. 2468-2473
  • Bromberg, J.F., Horvath, C.M., Besser, D., Lathem, W.W., Darnell Jr., J.E., Stat3 activation is required for cellular transformation by v-src (1998) Mol. Cell. Biol., 18, pp. 2553-2558
  • Bromberg, J.F., Wrzeszczynska, M.H., Devgan, G., Zhao, Y., Pestell, R.G., Albanese, C., Darnell Jr., J.E., Stat3 as an oncogene (1999) Cell, 98, pp. 295-303
  • Burke, W.M., Jin, X., Lin, H.J., Huang, M., Liu, R., Reynolds, R.K., Lin, J., Inhibition of constitutively active Stat3 suppresses growth of human ovarian and breast cancer cells (2001) Oncogene, 20, pp. 7925-7934
  • Castoria, G., Barone, M.V., Di Domenico, M., Bilancio, A., Ametrano, D., Migliaccio, A., Auricchio, F., Non-transcriptional action of oestradiol and progestin triggers DNA synthesis (1999) EMBO J., 18, pp. 2500-2510
  • Catlett-Falcone, R., Landowski, T.H., Oshiro, M.M., Turkson, J., Levitzki, A., Savino, R., Ciliberto, G., Jove, R., Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells (1999) Immunity, 10, pp. 105-115
  • Clarke, C.L., Sutherland, R.L., Progestin regulation of cellular proliferation (1990) Endocr. Rev., 11, pp. 266-301
  • Darnell Jr., J.E., Kerr, I.M., Stark, G.R., Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins (1994) Science, 264, pp. 1415-1421
  • Dechow, T.N., Pedranzini, L., Leitch, A., Leslie, K., Gerald, W.L., Linkov, I., Bromberg, J.F., Requirement of matrix metalloproteinase-9 for the transformation of human mammary epithelial cells by Stat3-C (2004) Proc. Natl. Acad. Sci. USA, 101, pp. 10602-10607
  • De Miguel, F., Lee, S.O., Onate, S.A., Gao, A.C., Stat3 enhances transactivation of steroid hormone receptors (2003) Nucl. Recept., 1, p. 3
  • Dran, G., Luthy, I.A., Molinolo, A.A., Montecchia, F., Charreau, E.H., Pasqualini, C.D., Lanari, C., Effect of medroxyprogesterone acetate (MPA) and serum factors on cell proliferation in primary cultures of an MPA-induced mammary adenocarcinoma (1995) Breast Cancer Res. Treat., 35, pp. 173-186
  • Garcia, R., Bowman, T.L., Niu, G., Yu, H., Minton, S., Muro-Cacho, C.A., Cox, C.E., Jove, R., Constitutive activation of Stat3 by the Src and JAK tyrosine kinases participates in growth regulation of human breast carcinoma cells (2001) Oncogene, 20, pp. 2499-2513
  • Groshong, S.D., Owen, G.I., Grimison, B., Schauer, I.E., Todd, M.C., Langan, T.A., Sclafani, R.A., Horwitz, K.B., Biphasic regulation of breast cancer cell growth by progesterone: Role of the cyclin-dependent kinase inhibitors, p21 and p27(Kip1) (1997) Mol. Endocrinol., 11, pp. 1593-1607
  • Jing, N., Li, Y., Xiong, W., Sha, W., Jing, L., Tweardy, D.J., G-quartet oligonucleotides: A new class of signal transducer and activator of transcription 3 inhibitors that suppresses growth of prostate and breast tumors through induction of apoptosis (2004) Cancer Res., 64, pp. 6603-6609
  • Kaptein, A., Paillard, V., Saunders, M., Dominant negative stat3 mutant inhibits interleukin-6-induced Jak-STAT signal transduction (1996) J. Biol. Chem., 271, pp. 5961-5964
  • Kiss, R., Paridaens, R.J., Heuson, J.C., Danguy, A.J., Effect of progesterone on cell proliferation in the MXT mouse hormone-sensitive mammary neoplasm (1986) J. Natl. Cancer Inst., 77, pp. 173-178
  • Labriola, L., Salatino, M., Proietti, C.J., Pecci, A., Coso, O.A., Kornblihtt, A.R., Charreau, E.H., Elizalde, P.V., Heregulin induces transcriptional activation of the progesterone receptor by a mechanism that requires functional ErbB-2 and mitogen-activated protein kinase activation in breast cancer cells (2003) Mol. Cell. Biol., 23, pp. 1095-1111
  • Lange, C.A., Richer, J.K., Shen, T., Horwitz, K.B., Convergence of progesterone and epidermal growth factor signaling in breast cancer. Potentiation of mitogen-activated protein kinase pathways (1998) J. Biol. Chem., 273, pp. 31308-31316
  • Leonhardt, S.A., Boonyaratanakornkit, V., Edwards, D.P., Progesterone receptor transcription and non-transcription signaling mechanisms (2003) Steroids, 68, pp. 761-770
  • Li, L., Shaw, P.E., Autocrine-mediated activation of STAT3 correlates with cell proliferation in breast carcinoma lines (2002) J. Biol. Chem., 277, pp. 17397-17405
  • Lin, V.C., Jin, R., Tan, P.H., Aw, S.E., Woon, C.T., Bay, B.H., Progesterone induces cellular differentiation in MDA-MB-231 breast cancer cells transfected with progesterone receptor complementary DNA (2003) Am. J. Pathol., 162, pp. 1781-1787
  • Liu, T., Ogle, T.F., Signal transducer and activator of transcription 3 is expressed in the decidualized mesometrium of pregnancy and associates with the progesterone receptor through protein-protein interactions (2002) Biol. Reprod., 67, pp. 114-118
  • Lydon, J.P., Sivaraman, L., Conneely, O.M., A reappraisal of progesterone action in the mammary gland (2000) J. Mammary Gland Biol. Neoplasia, 5, pp. 325-338
  • Manni, A., Badger, B., Wright, C., Ahmed, S.R., Demers, L.M., Effects of progestins on growth of experimental breast cancer in culture: Interaction with estradiol and prolactin and involvement of the polyamine pathway (1987) Cancer Res., 47, pp. 3066-3071
  • Migliaccio, A., Piccolo, D., Castoria, G., Di Domenico, M., Bilancio, A., Lombardi, M., Gong, W., Auricchio, F., Activation of the Src/p21ras/Erk pathway by progesterone receptor via cross-talk with estrogen receptor (1998) EMBO J., 17, pp. 2008-2018
  • Moore, M.R., Conover, J.L., Franks, K.M., Progestin effects on long-term growth, death, and Bcl-xL in breast cancer cells (2000) Biochem. Biophys. Res. Commun., 277, pp. 650-654
  • Niu, G., Heller, R., Catlett-Falcone, R., Coppola, D., Jaroszeski, M., Dalton, W., Jove, R., Yu, H., Gene therapy with dominant-negative Stat3 suppresses growth of the murine melanoma B16 tumor in vivo (1999) Cancer Res., 59, pp. 5059-5063
  • Niu, G., Shain, K.H., Huang, M., Ravi, R., Bedi, A., Dalton, W.S., Jove, R., Yu, H., Overexpression of a dominant-negative signal transducer and activator of transcription 3 variant in tumor cells leads to production of soluble factors that induce apoptosis and cell cycle arrest (2001) Cancer Res., 61, pp. 3276-3280
  • Niu, G., Wright, K.L., Huang, M., Song, L., Haura, E., Turkson, J., Zhang, S., Yu, H., Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis (2002) Oncogene, 21, pp. 2000-2008
  • Olayioye, M.A., Beuvink, I., Horsch, K., Daly, J.M., Hynes, N.E., ErbB receptor-induced activation of stat transcription factors is mediated by Src tyrosine kinases (1999) J. Biol. Chem., 274, pp. 17209-17218
  • Paukku, K., Valgeirsdottir, S., Saharinen, P., Bergman, M., Heldin, C.H., Silvennoinen, O., Platelet-derived growth factor (PDGF)-induced activation of signal transducer and activator of transcription (Stat) 5 is mediated by PDGF beta-receptor and is not dependent on c-src, fyn, jak1 or jak2 kinases (2000) Biochem. J., 345 (PART 3), pp. 759-766
  • Puricelli, L., Proiettii, C.J., Labriola, L., Salatino, M., Balana, M.E., Aguirre, G.J., Lupu, R., Elizalde, P.V., Heregulin inhibits proliferation via ERKs and phosphatidyl-inositol 3-kinase activation but regulates urokinase plasminogen activator independently of these pathways in metastatic mammary tumor cells (2002) Int. J. Cancer, 100, pp. 642-653
  • Real, P.J., Sierra, A., De Juan, A., Segovia, J.C., Lopez-Vega, J.M., Fernandez-Luna, J.L., Resistance to chemotherapy via Stat3-dependent overexpression of Bcl-2 in metastatic breast cancer cells (2002) Oncogene, 21, pp. 7611-7618
  • Ren, Z., Schaefer, T.S., ErbB-2 activates Stat3 alpha in a Src- and JAK2-dependent manner (2002) J. Biol. Chem., 277, pp. 38486-38493
  • Richer, J.K., Lange, C.A., Manning, N.G., Owen, G., Powell, R., Horwitz, K.B., Convergence of progesterone with growth factor and cytokine signaling in breast cancer. Progesterone receptors regulate signal transducers and activators of transcription expression and activity (1998) J. Biol. Chem., 273, pp. 31317-31326
  • Salatino, M., Schillaci, R., Proietti, C.J., Carnevale, R., Frahm, I., Molinolo, A.A., Iribarren, A., Elizalde, P.V., Inhibition of in vivo breast cancer growth by antisense oligodeoxynucleotides to type I insulin-like growth factor receptor mRNA involves inactivation of ErbBs, PI-3K/Akt and p42/p44 MAPK signaling pathways but not modulation of progesterone receptor activity (2004) Oncogene, 23, pp. 5161-5174
  • Sartor, C.I., Dziubinski, M.L., Yu, C.L., Jove, R., Ethier, S.P., Role of epidermal growth factor receptor and STAT-3 activation in autonomous proliferation of SUM-102PT human breast cancer cells (1997) Cancer Res., 57, pp. 978-987
  • Schaefer, L.K., Wang, S., Schaefer, T.S., Oncostatin M activates stat DNA binding and transcriptional activity in primary human fetal astrocytes: Low- and high-passage cells have distinct patterns of stat activation (2000) Cytokine, 12, pp. 1647-1655
  • Schulze, H., Ballmaier, M., Welte, K., Germeshausen, M., Thrombopoietin induces the generation of distinct Stat1, Stat3, Stat5a and Stat5b homo- and heterodimeric complexes with different kinetics in human platelets (2000) Exp. Hematol., 28, pp. 294-304
  • Shen, T., Horwitz, K.B., Lange, C.A., Transcriptional hyperactivity of human progesterone receptors is coupled to their ligand-dependent downregulation by mitogen-activated protein kinase-dependent phosphorylation of serine 294 (2001) Mol. Cell. Biol., 21, pp. 6122-6131
  • Sherman, C.T., Brasier, A.R., Role of signal transducers and activators of transcription 1 and 3 in inducible regulation of the human angiotensinogen gene by interleukin-6 (2001) Mol. Endocrinol., 15, pp. 441-457
  • Silvennoinen, O., Schindler, C., Schlessinger, J., Levy, D.E., Ras-independent growth factor signaling by transcription factor tyrosine phosphorylation (1993) Science, 261, pp. 1736-1739
  • Stoecklin, E., Wissler, M., Schaetzle, D., Pfitzner, E., Groner, B., Interactions in the transcriptional regulation exerted by Stat5 and by members of the steroid hormone receptor family (1999) J. Steroid Biochem. Mol. Biol., 69, pp. 195-204
  • Taga, T., Kishimoto, T., Gp130 and the interleukin-6 family of cytokines (1997) Annu. Rev. Immunol., 15, pp. 797-819
  • Vultur, A., Cao, J., Arulanandam, R., Turkson, J., Jove, R., Greer, P., Craig, A., Raptis, L., Cell-to-cell adhesion modulates Stat3 activity in normal and breast carcinoma cells (2004) Oncogene, 23, pp. 2600-2616
  • Wang, T., Niu, G., Kortylewski, M., Burdelya, L., Shain, K., Zhang, S., Bhattacharya, R., Yu, H., Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells (2004) Nat. Med., 10, pp. 48-54
  • Yu, H., Jove, R., The STATs of cancer-new molecular targets come of age (2004) Nat. Rev. Cancer, 4, pp. 97-105
  • Zhang, X., Wrzeszczynska, M.H., Horvath, C.M., Darnell Jr., J.E., Interacting regions in Stat3 and c-Jun that participate in cooperative transcriptional activation (1999) Mol. Cell. Biol., 19, pp. 7138-7146
  • Zhang, Y., Turkson, J., Carter-Su, C., Smithgall, T., Levitzki, A., Kraker, A., Krolewski, J.J., Jove, R., Activation of Stat3 in v-Src-transformed fibroblasts requires cooperation of Jak1 kinase activity (2000) J. Biol. Chem., 275, pp. 24935-24944
  • Zhang, Z., Jones, S., Hagood, J.S., Fuentes, N.L., Fuller, G.M., STAT3 acts as a co-activator of glucocorticoid receptor signaling (1997) J. Biol. Chem., 272, pp. 30607-30610
  • Zhu, Y., Bond, J., Thomas, P., Identification, classification, and partial characterization of genes in humans and other vertebrates homologous to a fish membrane progestin receptor (2003) Proc. Natl. Acad. Sci. USA, 100, pp. 2237-2242

Citas:

---------- APA ----------
Proietti, C., Salatino, M., Rosemblit, C., Carnevale, R., Pecci, A., Kornblihtt, A.R., Molinolo, A.A.,..., Elizalde, P.V. (2005) . Progestins induce transcriptional activation of signal transducer and activator of transcription 3 (Stat3) via a Jak- and Src-dependent mechanism in breast cancer cells. Molecular and Cellular Biology, 25(12), 4826-4840.
http://dx.doi.org/10.1128/MCB.25.12.4826-4840.2005
---------- CHICAGO ----------
Proietti, C., Salatino, M., Rosemblit, C., Carnevale, R., Pecci, A., Kornblihtt, A.R., et al. "Progestins induce transcriptional activation of signal transducer and activator of transcription 3 (Stat3) via a Jak- and Src-dependent mechanism in breast cancer cells" . Molecular and Cellular Biology 25, no. 12 (2005) : 4826-4840.
http://dx.doi.org/10.1128/MCB.25.12.4826-4840.2005
---------- MLA ----------
Proietti, C., Salatino, M., Rosemblit, C., Carnevale, R., Pecci, A., Kornblihtt, A.R., et al. "Progestins induce transcriptional activation of signal transducer and activator of transcription 3 (Stat3) via a Jak- and Src-dependent mechanism in breast cancer cells" . Molecular and Cellular Biology, vol. 25, no. 12, 2005, pp. 4826-4840.
http://dx.doi.org/10.1128/MCB.25.12.4826-4840.2005
---------- VANCOUVER ----------
Proietti, C., Salatino, M., Rosemblit, C., Carnevale, R., Pecci, A., Kornblihtt, A.R., et al. Progestins induce transcriptional activation of signal transducer and activator of transcription 3 (Stat3) via a Jak- and Src-dependent mechanism in breast cancer cells. Mol. Cell. Biol. 2005;25(12):4826-4840.
http://dx.doi.org/10.1128/MCB.25.12.4826-4840.2005