The transcriptional responsiveness of LKB1 to STAT-mediated signaling is differentially modulated by prolactin in human breast cancer cells

BMC Cancer

Katja Linher-Melville¹  Gurmit Singh¹ 

[1] Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada

关键词: Transcriptional regulation;    Promoter;    Interleukin 6;    Prolactin;    LKB1;    STAT5;    STAT3;    Breast cancer;   

Others  :  857320
DOI  :  10.1186/1471-2407-14-415

 received in 2013-12-13, accepted in 2014-05-27,  发布年份 2014

【 摘 要 】

Background

Liver kinase 1 (LKB1) is an important multi-tasking protein linked with metabolic signaling, also controlling polarity and cytoskeletal rearrangements in diverse cell types including cancer cells. Prolactin (PRL) and Signal transducer and activator of transcription (STAT) proteins have been associated with breast cancer progression. The current investigation examines the effect of PRL and STAT-mediated signaling on the transcriptional regulation of LKB1 expression in human breast cancer cells.

Methods

MDA-MB-231, MCF-7, and T47D human breast cancer cells, and CHO-K1 cells transiently expressing the PRL receptor (long form), were treated with 100 ng/ml of PRL for 24 hours. A LKB1 promoter-luciferase construct and its truncations were used to assess transcriptional changes in response to specific siRNAs or inhibitors targeting Janus activated kinase 2 (JAK2), STAT3, and STAT5A. Real-time PCR and Western blotting were applied to quantify changes in mRNA and protein levels. Electrophoretic mobility shift (EMSA) and chromatin immunoprecipitation (ChIP) assays were used to examine STAT3 and STAT5A binding to the LKB1 promoter.

Results

Consistent with increases in mRNA, the LKB1 promoter was up-regulated by PRL in MDA-MB-231 cells, a response that was lost upon distal promoter truncation. A putative GAS element that could provide a STAT binding site mapped to this region, and its mutation decreased PRL-responsiveness. PRL-mediated increases in promoter activity required signaling through STAT3 and STAT5A, also involving JAK2. Both STATs imparted basally repressive effects in MDA-MB-231 cells. PRL increased in vivo binding of STAT3, and more definitively, STAT5A, to the LKB1 promoter region containing the GAS site. In T47D cells, PRL down-regulated LKB1 transcriptional activity, an effect that was reversed upon culture in phenol red-free media. Interleukin 6, a cytokine activating STAT signaling in diverse cell types, also increased LKB1 mRNA levels and promoter activity in MDA-MB-231 cells.

Conclusions

LKB1 is differentially regulated by PRL at the level of transcription in representative human breast cancer cells. Its promoter is targeted by STAT proteins, and the cellular estrogen receptor status may affect PRL-responsiveness. The hormonal and possibly cytokine-mediated control of LKB1 expression is particularly relevant in aggressive breast cancer cells, potentially promoting survival under energetically unfavorable conditions.

【 授权许可】

   
2014 Linher-Melville and Singh; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Trott JF, Schennink A, Petrie WK, Manjarin R, VanKlompenberg MK, Hovey RC: Triennial lactation symposium: prolactin: the multifaceted potentiator of mammary growth and function. J Anim Sci 2012, 90(5):1674-1686.
• [2]Ben-Jonathan N, Hugo ER, Brandebourg TD, LaPensee CR: Focus on prolactin as a metabolic hormone. Trends Endocrinol Metab 2006, 17(3):110-116.
• [3]Bole-Feysot C, Goffin V, Edery M, Binart N, Kelly PA: Prolactin (PRL) and its receptor: actions, signal transduction pathways and phenotypes observed in PRL receptor knockout mice. Endocr Rev 1998, 19(3):225-268.
• [4]Brandebourg T, Hugo E, Ben-Jonathan N: Adipocyte prolactin: regulation of release and putative functions. Diabetes Obes Metab 2007, 9(4):464-476.
• [5]Clevenger CV, Freier DO, Kline JB: Prolactin receptor signal transduction in cells of the immune system. J Endocrinol 1998, 157(2):187-197.
• [6]Ben-Jonathan N, Liby K, McFarland M, Zinger M: Prolactin as an autocrine/paracrine growth factor in human cancer. Trends Endocrinol Metab 2002, 13(6):245-250.
• [7]Carver KC, Arendt LM, Schuler LA: Complex prolactin crosstalk in breast cancer: new therapeutic implications. Mol Cell Endocrinol 2009, 307(1–2):1-7.
• [8]Harvey PW: Hypothesis: prolactin is tumorigenic to human breast: dispelling the myth that prolactin-induced mammary tumors are rodent-specific. J Appl Toxicol 2012, 32(1):1-9.
• [9]Maus MV, Reilly SC, Clevenger CV: Prolactin as a chemoattractant for human breast carcinoma. Endocrinology 1999, 140(11):5447-5450.
• [10]Clevenger CV, Furth PA, Hankinson SE, Schuler LA: The role of prolactin in mammary carcinoma. Endocr Rev 2003, 24(1):1-27.
• [11]Luo G, Yu-Lee L: Transcriptional inhibition by Stat5. differential activities at growth-related versus differentiation-specific promoters. J Biol Chem 1997, 272(43):26841-26849.
• [12]O’Shea JJ, Gadina M, Schreiber RD: Cytokine signaling in 2002: new surprises in the Jak/Stat pathway. Cell 2002, 109(Suppl):S121-S131.
• [13]Darnell JE Jr: STATs and gene regulation. Science 1997, 277(5332):1630-1635.
• [14]Ihle JN: STATs: signal transducers and activators of transcription. Cell 1996, 84(3):331-334.
• [15]Sakamoto K, Lin WC, Triplett AA, Wagner KU: Targeting janus kinase 2 in Her2/neu-expressing mammary cancer: implications for cancer prevention and therapy. Cancer Res 2009, 69(16):6642-6650.
• [16]Sakamoto K, Triplett AA, Schuler LA, Wagner KU: Janus kinase 2 is required for the initiation but not maintenance of prolactin-induced mammary cancer. Oncogene 2010, 29(39):5359-5369.
• [17]Walker SR, Nelson EA, Zou L, Chaudhury M, Signoretti S, Richardson A, Frank DA: Reciprocal effects of STAT5 and STAT3 in breast cancer. Mol Cancer Res 2009, 7(6):966-976.
• [18]Endo TA, Masuhara M, Yokouchi M, Suzuki R, Sakamoto H, Mitsui K, Matsumoto A, Tanimura S, Ohtsubo M, Misawa H, Miyazaki T, Leonor N, Taniguchi T, Fujita T, Kanakura Y, Komiya S, Yoshimura A: A new protein containing an SH2 domain that inhibits JAK kinases. Nature 1997, 387(6636):921-924.
• [19]Starr R, Willson TA, Viney EM, Murray LJ, Rayner JR, Jenkins BJ, Gonda TJ, Alexander WS, Metcalf D, Nicola NA, Hilton DJ: A family of cytokine-inducible inhibitors of signalling. Nature 1997, 387(6636):917-921.
• [20]Chung CD, Liao J, Liu B, Rao X, Jay P, Berta P, Shuai K: Specific inhibition of Stat3 signal transduction by PIAS3. Science 1997, 278(5344):1803-1805.
• [21]Fan D, Ma C, Zhang H: The molecular mechanisms that underlie the tumor suppressor function of LKB1. Acta Biochim Biophys Sin 2009, 41(2):97-107.
• [22]Ji H, Ramsey MR, Hayes DN, Fan C, McNamara K, Kozlowski P, Torrice C, Wu MC, Shimamura T, Perera SA, Liang MC, Cai D, Naumov GN, Bao L, Contreras CM, Li D, Chen L, Krishnamurthy J, Koivunen J, Chirieac LR, Padera RF, Bronson RT, Lindeman NI, Christiani DC, Lin X, Shapiro GI, Janne PA, Johnson BE, Meyerson M, Kwiatkowski DJ: LKB1 modulates lung cancer differentiation and metastasis. Nature 2007, 448(7155):807-810.
• [23]Alessi DR, Sakamoto K, Bayascas JR: LKB1-dependent signaling pathways. Annu Rev Biochem 2006, 75:137-163.
• [24]Mukherjee P, Mulrooney TJ, Marsh J, Blair D, Chiles TC, Seyfried TN: Differential effects of energy stress on AMPK phosphorylation and apoptosis in experimental brain tumor and normal brain. Mol Cancer 2008, 7:37. BioMed Central Full Text
• [25]Shaw RJ, Kosmatka M, Bardeesy N, Hurley RL, Witters LA, DePinho RA, Cantley LC: The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc Natl Acad Sci U S A 2004, 101(10):3329-3335.
• [26]Linher-Melville K, Zantinge S, Sanli T, Gerstein H, Tsakiridis T, Singh G: Establishing a relationship between prolactin and altered fatty acid beta-oxidation via carnitine palmitoyl transferase 1 in breast cancer cells. BMC Cancer 2011, 11:56. BioMed Central Full Text
• [27]Esteller M, Avizienyte E, Corn PG, Lothe RA, Baylin SB, Aaltonen LA, Herman JG: Epigenetic inactivation of LKB1 in primary tumors associated with the Peutz-Jeghers syndrome. Oncogene 2000, 19(1):164-168.
• [28]Trojan J, Brieger A, Raedle J, Esteller M, Zeuzem S: 5'-CpG island methylation of the LKB1/STK11 promoter and allelic loss at chromosome 19p13.3 in sporadic colorectal cancer. Gut 2000, 47(2):272-276.
• [29]Linher-Melville K, Zantinge S, Singh G: Liver kinase B1 expression (LKB1) is repressed by estrogen receptor alpha (ERalpha) in MCF-7 human breast cancer cells. Biochem Biophys Res Commun 2012, 417(3):1063-1068.
• [30]Schmitt-Ney M, Doppler W, Ball RK, Groner B: Beta-casein gene promoter activity is regulated by the hormone-mediated relief of transcriptional repression and a mammary-gland-specific nuclear factor. Mol Cell Biol 1991, 11(7):3745-3755.
• [31]Schmitt-Ney M, Happ B, Ball RK, Groner B: Developmental and environmental regulation of a mammary gland-specific nuclear factor essential for transcription of the gene encoding beta-casein. Proc Natl Acad Sci U S A 1992, 89(7):3130-3134.
• [32]Brockman JL, Schroeder MD, Schuler LA: PRL activates the cyclin D1 promoter via the Jak2/Stat pathway. Mol Endocrinol 2002, 16(4):774-784.
• [33]Brockman JL, Schuler LA: Prolactin signals via Stat5 and Oct-1 to the proximal cyclin D1 promoter. Mol Cell Endocrinol 2005, 239(1–2):45-53.
• [34]Hogan JC, Stephens JM: The regulation of fatty acid synthase by STAT5A. Diabetes 2005, 54(7):1968-1975.
• [35]White UA, Coulter AA, Miles TK, Stephens JM: The STAT5A-mediated induction of pyruvate dehydrogenase kinase 4 expression by prolactin or growth hormone in adipocytes. Diabetes 2007, 56(6):1623-1629.
• [36]Boutin JM, Edery M, Shirota M, Jolicoeur C, Lesueur L, Ali S, Gould D, Djiane J, Kelly PA: Identification of a cDNA encoding a long form of prolactin receptor in human hepatoma and breast cancer cells. Mol Endocrinol 1989, 3(9):1455-1461.
• [37]Ginsburg E, Alexander S, Lieber S, Tarplin S, Jenkins L, Pang L, Heger CD, Goldsmith P, Vonderhaar BK: Characterization of ductal and lobular breast carcinomas using novel prolactin receptor isoform specific antibodies. BMC Cancer 2010, 10:678. BioMed Central Full Text
• [38]Ueda E, Ozerdem U, Chen YH, Yao M, Huang KT, Sun H, Martins-Green M, Bartolini P, Walker AM: A molecular mimic demonstrates that phosphorylated human prolactin is a potent anti-angiogenic hormone. Endocr Relat Cancer 2006, 13(1):95-111.
• [39]Livak KJ, Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001, 25(4):402-408.
• [40]Linher K, Cheung Q, Baker P, Bedecarrats G, Shiota K, Li J: An epigenetic mechanism regulates germ cell-specific expression of the porcine Deleted in Azoospermia-Like (DAZL) gene. Differentiation; research in biological diversity 2009, 77(4):335-349.
• [41]Horvath CM, Wen Z, Darnell JE Jr: A STAT protein domain that determines DNA sequence recognition suggests a novel DNA-binding domain. Genes Dev 1995, 9(8):984-994.
• [42]Schindler U, Wu P, Rothe M, Brasseur M, McKnight SL: Components of a Stat recognition code: evidence for two layers of molecular selectivity. Immunity 1995, 2(6):689-697.
• [43]Moon C, Yoo JY, Matarazzo V, Sung YK, Kim EJ, Ronnett GV: Leukemia inhibitory factor inhibits neuronal terminal differentiation through STAT3 activation. Proc Natl Acad Sci U S A 2002, 99(13):9015-9020.
• [44]Ferrajoli A, Faderl S, Van Q, Koch P, Harris D, Liu Z, Hazan-Halevy I, Wang Y, Kantarjian HM, Priebe W, Estrov Z: WP1066 disrupts Janus kinase-2 and induces caspase-dependent apoptosis in acute myelogenous leukemia cells. Cancer Res 2007, 67(23):11291-11299.
• [45]Yang L, Perez AA, Fujie S, Warden C, Li J, Wang Y, Yung B, Chen YR, Liu X, Zhang H, Zheng S, Liu Z, Ann D, Yen Y: Wnt modulates MCL1 to control cell survival in triple negative breast cancer. BMC Cancer 2014, 14:124. BioMed Central Full Text
• [46]Martin-Belmonte F, Perez-Moreno M: Epithelial cell polarity, stem cells and cancer. Nat Rev Cancer 2012, 12(1):23-38.
• [47]Ossipova O, Bardeesy N, DePinho RA, Green JB: LKB1 (XEEK1) regulates Wnt signalling in vertebrate development. Nat Cell Biol 2003, 5(10):889-894.
• [48]Ma Y, Zhang G, Fu X, Xia O, Zhan C, Li L, Wang Z, Wu B: Wnt signaling may be activated in a subset of Peutz-Jeghers syndrome polyps closely correlating to LKB1 expression. Oncol Rep 2010, 23(6):1569-1576.
• [49]Sun G, Reynolds R, Leclerc I, Rutter GA: RIP2-mediated LKB1 deletion causes axon degeneration in the spinal cord and hind-limb paralysis. Dis Model Mech 2011, 4(2):193-202.
• [50]Hezel AF, Gurumurthy S, Granot Z, Swisa A, Chu GC, Bailey G, Dor Y, Bardeesy N, Depinho RA: Pancreatic LKB1 deletion leads to acinar polarity defects and cystic neoplasms. Mol Cell Biol 2008, 28(7):2414-2425.
• [51]Jacob LS, Wu X, Dodge ME, Fan CW, Kulak O, Chen B, Tang W, Wang B, Amatruda JF, Lum L: Genome-wide RNAi screen reveals disease-associated genes that are common to Hedgehog and Wnt signaling. Sci Signal 2011, 4(157):ra4.
• [52]Green JB: Lkb1 and GSK3-beta: kinases at the center and poles of the action. Cell Cycle 2004, 3(1):12-14.
• [53]Nouhi Z, Chughtai N, Hartley S, Cocolakis E, Lebrun JJ, Ali S: Defining the role of prolactin as an invasion suppressor hormone in breast cancer cells. Cancer Res 2006, 66(3):1824-1832.
• [54]Collares-Buzato CB, Leite AR, Boschero AC: Modulation of gap and adherens junctional proteins in cultured neonatal pancreatic islets. Pancreas 2001, 23(2):177-185.
• [55]Phoenix KN, Vumbaca F, Claffey KP: Therapeutic metformin/AMPK activation promotes the angiogenic phenotype in the ERalpha negative MDA-MB-435 breast cancer model. Breast Cancer Res Treat 2009, 113(1):101-111.
• [56]Shen Z, Wen XF, Lan F, Shen ZZ, Shao ZM: The tumor suppressor gene LKB1 is associated with prognosis in human breast carcinoma. Clin Cancer Res 2002, 8(7):2085-2090.
• [57]Nagalingam A, Arbiser JL, Bonner MY, Saxena NK, Sharma D: Honokiol activates AMP-activated protein kinase in breast cancer cells via an LKB1-dependent pathway and inhibits breast carcinogenesis. Breast Cancer Res 2012, 14(1):R35. BioMed Central Full Text
• [58]Gill S, Peston D, Vonderhaar BK, Shousha S: Expression of prolactin receptors in normal, benign, and malignant breast tissue: an immunohistological study. J Clin Pathol 2001, 54(12):956-960.
• [59]Reynolds C, Montone KT, Powell CM, Tomaszewski JE, Clevenger CV: Expression of prolactin and its receptor in human breast carcinoma. Endocrinology 1997, 138(12):5555-5560.
• [60]Ballestar E, Paz MF, Valle L, Wei S, Fraga MF, Espada J, Cigudosa JC, Huang TH, Esteller M: Methyl-CpG binding proteins identify novel sites of epigenetic inactivation in human cancer. EMBO J 2003, 22(23):6335-6345.
• [61]Ginsburg E, Heger CD, Goldsmith P, Vonderhaar BK: Prolactin receptor isoforms in human breast cancer. In Prolactin Edited by Nagy GM. 2013. http://www.intechopen.com/books/prolactin/prolactin-receptor-isoforms-in-human-breast-cancer: webcite InTech; 2013
• [62]Ding W, Wu W: Multiple human prolactin receptors and signaling. Afr J Biotechnol 2010, 9(7):940-949.
• [63]Fang F, Rycyzyn MA, Clevenger CV: Role of c-Myb during prolactin-induced signal transducer and activator of transcription 5a signaling in breast cancer cells. Endocrinology 2009, 150(4):1597-1606.
• [64]Johnson KJ, Peck AR, Liu C, Tran TH, Utama FE, Sjolund AB, Schaber JD, Witkiewicz AK, Rui H: PTP1B suppresses prolactin activation of Stat5 in breast cancer cells. Am J Pathol 2010, 177(6):2971-2983.
• [65]Wu W, Sun M, Zhang HP, Chen T, Wu R, Liu C, Yang G, Geng XR, Feng BS, Liu Z, Yang PC: Prolactin mediates psychological stress-induced dysfunction of regulatory T cells to facilitate intestinal inflammation. Gut 2014. Epub ahead of print
• [66]Yin K: The Mesenchymal-Like Phenotype of the MDA-MB-231 Cell Line. In Breast Cancer - Focusing Tumor Microenvironment, Stem cells and Metastasis. 18th edition. Edited by Gunduz MG. InTech; 2011:584. http://www.intechopen.com/books/breast-cancer-focusing-tumor-microenvironment-stem-cells-and-metastasis/the-mesenchymal-like-phenotype-of-the-mda-mb-231-cell-line webcite
• [67]Wakao H, Gouilleux F, Groner B: Mammary gland factor (MGF) is a novel member of the cytokine regulated transcription factor gene family and confers the prolactin response. EMBO J 1994, 13(9):2182-2191.
• [68]Zhu T, Lobie PE: Janus kinase 2-dependent activation of p38 mitogen-activated protein kinase by growth hormone. Resultant transcriptional activation of ATF-2 and CHOP, cytoskeletal re-organization and mitogenesis. J Biol Chem 2000, 275(3):2103-2114.
• [69]Decker T, Kovarik P: Serine phosphorylation of STATs. Oncogene 2000, 19(21):2628-2637.
• [70]Goldhar AS, Vonderhaar BK, Trott JF, Hovey RC: Prolactin-induced expression of vascular endothelial growth factor via Egr-1. Mol Cell Endocrinol 2005, 232(1–2):9-19.
• [71]Gray MJ, Zhang J, Ellis LM, Semenza GL, Evans DB, Watowich SS, Gallick GE: HIF-1alpha, STAT3, CBP/p300 and Ref-1/APE are components of a transcriptional complex that regulates Src-dependent hypoxia-induced expression of VEGF in pancreatic and prostate carcinomas. Oncogene 2005, 24(19):3110-3120.
• [72]Shin J, Lee HJ, Jung DB, Jung JH, Lee EO, Lee SG, Shim BS, Choi SH, Ko SG, Ahn KS, Jeong SJ, Kim SH: Suppression of STAT3 and HIF-1 alpha mediates anti-angiogenic activity of betulinic acid in hypoxic PC-3 prostate cancer cells. PLoS One 2011, 6(6):e21492.
• [73]Nakajima KI, Nakamura M, Ishisaki A, Kozakai T: Synergistic effect of Dexamethasone and Prolactin on VEGF expression in Bovine Mammary Epithelial Cells via p44/p42 MAP Kinase. Asian Austral J Anim 2009, 22(6):788-793.
• [74]Londesborough A, Vaahtomeri K, Tiainen M, Katajisto P, Ekman N, Vallenius T, Makela TP: LKB1 in endothelial cells is required for angiogenesis and TGFbeta-mediated vascular smooth muscle cell recruitment. Development 2008, 135(13):2331-2338.
• [75]Rajendran KG, Lopez T, Parikh I: Estrogenic effect of phenol red in MCF-7 cells is achieved through activation of estrogen receptor by interacting with a site distinct from the steroid binding site. Biochem Biophys Res Commun 1987, 142(3):724-731.
• [76]Frasor J, Gibori G: Prolactin regulation of estrogen receptor expression. Trends Endocrinol Metab 2003, 14(3):118-123.
• [77]Wang LH, Yang XY, Zhang X, Farrar WL: Nuclear receptors as negative modulators of STAT3 in multiple myeloma. Cell Cycle 2005, 4(2):242-245.
• [78]Yamamoto T, Matsuda T, Junicho A, Kishi H, Saatcioglu F, Muraguchi A: Cross-talk between signal transducer and activator of transcription 3 and estrogen receptor signaling. FEBS Lett 2000, 486(2):143-148.
• [79]Brown KA, McInnes KJ, Takagi K, Ono K, Hunger NI, Wang L, Sasano H, Simpson ER: LKB1 expression is inhibited by estradiol-17beta in MCF-7 cells. J Steroid Biochem Mol Biol 2011, 127(3–5):439-443.
• [80]Lim EJ, Hong DY, Park JH, Joung YH, Darvin P, Kim SY, Na YM, Hwang TS, Ye SK, Moon ES, Cho BW, Do Park K, Lee HK, Park T, Yang YM: Methylsulfonylmethane suppresses breast cancer growth by down-regulating STAT3 and STAT5b pathways. PLoS One 2012, 7(4):e33361.
• [81]Peck AR, Witkiewicz AK, Liu C, Klimowicz AC, Stringer GA, Pequignot E, Freydin B, Yang N, Ertel A, Tran TH, Girondo MA, Rosenberg AL, Hooke JA, Kovatich AJ, Shriver CD, Rimm DL, Magliocco AM, Hyslop T, Rui H: Low levels of Stat5a protein in breast cancer are associated with tumor progression and unfavorable clinical outcomes. Breast Cancer Res 2012, 14(5):R130. BioMed Central Full Text
• [82]Britschgi A, Andraos R, Brinkhaus H, Klebba I, Romanet V, Muller U, Murakami M, Radimerski T, Bentires-Alj M: JAK2/STAT5 inhibition circumvents resistance to PI3K/mTOR blockade: a rationale for cotargeting these pathways in metastatic breast cancer. Cancer Cell 2012, 22(6):796-811.
• [83]Gu L, Vogiatzi P, Puhr M, Dagvadorj A, Lutz J, Ryder A, Addya S, Fortina P, Cooper C, Leiby B, Dasgupta A, Hyslop T, Bubendorf L, Alanen K, Mirtti T, Nevalainen MT: Stat5 promotes metastatic behavior of human prostate cancer cells in vitro and in vivo. Endocr Relat Cancer 2010, 17(2):481-493.
• [84]Timofeeva OA, Tarasova NI, Zhang X, Chasovskikh S, Cheema AK, Wang H, Brown ML, Dritschilo A: STAT3 suppresses transcription of proapoptotic genes in cancer cells with the involvement of its N-terminal domain. Proc Natl Acad Sci U S A 2013, 110(4):1267-1272.
• [85]Sen B, Peng S, Woods DM, Wistuba I, Bell D, El-Naggar AK, Lai SY, Johnson FM: STAT5A-mediated SOCS2 expression regulates Jak2 and STAT3 activity following c-Src inhibition in head and neck squamous carcinoma. Clin Cancer Res 2012, 18(1):127-139.
• [86]Leslie K, Gao SP, Berishaj M, Podsypanina K, Ho H, Ivashkiv L, Bromberg J: Differential interleukin-6/Stat3 signaling as a function of cellular context mediates Ras-induced transformation. Breast Cancer Res 2010, 12(5):R80. BioMed Central Full Text