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• W2046604039 abstract "The intracellular signals driving the proliferation of breast carcinoma (BC) cells have been widely studied. Both the mitotic and metastatic potential of BC cells have been linked to the frequent overexpression of ErbB family members. Other signaling molecules, including the estrogen receptor, the tyrosine kinases c-Src and Syk, and STAT proteins, especially STAT3, have also been implicated in BC tumor growth. Here we have examined ErbB and STAT protein expression and activation in six BC-derived cell lines. ErbB expression and tyrosine phosphorylation varied considerably among the six cell lines. However, STAT protein expression and activation were more consistent. Two levels of STAT3 activation were distinguished in DNA-binding assays: an epidermal growth factor-inducible, high level that requires both ErbB1 and Janus kinase (JAK) activity and an elevated serum-dependent level that is maintained by autocrine/paracrine signaling and requires JAK activity but is independent of ErbB1 kinase activity. BC cell growth could be inhibited by dominant-negative versions of STAT3 and the JAK inhibitor AG490 but not by PD153035 or PD168393, inhibitors of ErbB1 kinase activity. This indicates that BC cell proliferation may be a consequence of STAT3 activation by autocrine/paracrine signals. The intracellular signals driving the proliferation of breast carcinoma (BC) cells have been widely studied. Both the mitotic and metastatic potential of BC cells have been linked to the frequent overexpression of ErbB family members. Other signaling molecules, including the estrogen receptor, the tyrosine kinases c-Src and Syk, and STAT proteins, especially STAT3, have also been implicated in BC tumor growth. Here we have examined ErbB and STAT protein expression and activation in six BC-derived cell lines. ErbB expression and tyrosine phosphorylation varied considerably among the six cell lines. However, STAT protein expression and activation were more consistent. Two levels of STAT3 activation were distinguished in DNA-binding assays: an epidermal growth factor-inducible, high level that requires both ErbB1 and Janus kinase (JAK) activity and an elevated serum-dependent level that is maintained by autocrine/paracrine signaling and requires JAK activity but is independent of ErbB1 kinase activity. BC cell growth could be inhibited by dominant-negative versions of STAT3 and the JAK inhibitor AG490 but not by PD153035 or PD168393, inhibitors of ErbB1 kinase activity. This indicates that BC cell proliferation may be a consequence of STAT3 activation by autocrine/paracrine signals. The mitogenic potential of ErbB family members has been implicated in the genesis of a variety of human carcinomas, and in the majority of BC cases, overexpression of ErbB proteins is detected. The epidermal growth factor receptor (ErbB1) is found overexpressed in some cancers, as is ErbB3, and ErbB1 has been shown to be tumorigenic in murine fibroblasts when overexpressed, but notably, only when activated by ligand (1Velu T.J. Beguinot L. Vass W.C. Willingham M.C. Merlino G.T. Pastan I. Lowy D.R. Science. 1987; 238: 1408-1410Crossref PubMed Scopus (350) Google Scholar). ErbB2 is overexpressed in a wide range of human tumors as a result of gene amplification or transcriptional activation. Thirty percent of invasive breast carcinomas overexpress ErbB2, and this correlates with a poor prognosis (2Lupu R. Cardillo M. Harris L. Hijazi M. Rosenberg K. Semin. Cancer Biol. 1995; 6: 135-145Crossref PubMed Scopus (57) Google Scholar). Indeed, ErbB2 is the only member of the ErbB family for which no ligand has been identified and the only receptor tyrosine kinase that, in the absence of ligand, appears to cause transformation when overexpressed in NIH3T3 cells (3Hynes N.E. Stern D.F. Biochim. Biophys. Acta. 1994; 1198: 165-184Crossref PubMed Scopus (998) Google Scholar, 4Difiore P.P. Pierce J.H. Kraus M.H. Segatto O. King C.R. Aaronson S.A. Science. 1987; 237: 178-182Crossref PubMed Scopus (861) Google Scholar, 5Hudziak R.M. Schlessinger J. Ullrich A. Proc. Natl. Acad. Sci. U. S. A. 1987; 84: 7159-7163Crossref PubMed Scopus (548) Google Scholar). The link between ErbB2 and oncogenesis has therefore been the subject of much consideration.Overexpression of ErbB2 is sufficient to cause its hyperphosphorylation, which may trigger signaling and transformation (6Stern D.F. Kamps M.P. Cao H. Mol. Cell. Biol. 1988; 8: 3969-3973Crossref PubMed Scopus (125) Google Scholar). Alternatively, ErbB2 overexpression may enhance the binding affinities of both EGF 1The abbreviations used are: EGFepidermal growth factorSTATsignal transducers and activators of transcriptionJAKJanus kinaseEMSAelectrophoretic mobility shift assayPVDFpolyvinylidene difluoridePBSphosphate-buffered salineFCSfetal calf serumSIEv-Sis-inducible elementGFPgreen fluorescent protein 1The abbreviations used are: EGFepidermal growth factorSTATsignal transducers and activators of transcriptionJAKJanus kinaseEMSAelectrophoretic mobility shift assayPVDFpolyvinylidene difluoridePBSphosphate-buffered salineFCSfetal calf serumSIEv-Sis-inducible elementGFPgreen fluorescent protein and neu differentiation factor for their ligands, thereby amplifying subsequent downstream signals. Thus, ErbB2 overexpression may allow tumor cells to respond to low concentrations of mitogenic growth factors (7Karunagaran D. Tzahar E. Beerli R.R. Chen X. Graus-Porta D. Ratzkin B.J. Seger R. Hynes N.E. Yarden Y. EMBO J. 1996; 15: 254-264Crossref PubMed Scopus (585) Google Scholar). However, in vitro assays indicate that although low levels of neu differentiation factor increase the growth rate of cancer cell lines overexpressing ErbB2, higher levels result in anti-proliferative and differentiating effects (2Lupu R. Cardillo M. Harris L. Hijazi M. Rosenberg K. Semin. Cancer Biol. 1995; 6: 135-145Crossref PubMed Scopus (57) Google Scholar).Analyses of transgenic mice carrying ErbB2 have indicated that its overexpression alone is insufficient to cause malignancies, since those detected could be attributed to somatic activating mutations in the extracellular domain of ErbB2 (8Siegel P.M. Dankort D.L. Hardy W.R. Muller W.J. Mol. Cell. Biol. 1994; 14: 7068-7077Crossref PubMed Scopus (187) Google Scholar). Subsequent work revealed a splice variant of ErbB2 in human BC samples with in vitro transforming potential (9Siegel P.M. Ryan E.D. Cardiff R.D. Muller W.J. EMBO J. 1999; 18: 2149-2164Crossref PubMed Scopus (369) Google Scholar). However, other factors may contribute to tumorigenesis mediated by ErbB overexpression. For example, c-Src, which is also overexpressed in BC (10Ottenhoff-Kalff A.E. Rijksen G. van Beurden E.A.C.M. Hennipman A. Michels A.A. Staal G.E.J. Cancer Res. 1992; 52: 4773-4778PubMed Google Scholar), is able to synergize with ErbB1 to transform cells (11Tice D.A. Biscardi J.S. Nickles A.L. Parsons S.J. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 1415-1420Crossref PubMed Scopus (397) Google Scholar), possibly by c-Src-mediated receptor phosphorylation (12Biscardi J.S. Maa M.-C. Tice D.A. Cox M.E. Leu T.-H. Parsons S.J. J. Biol. Chem. 1999; 274: 8335-8343Abstract Full Text Full Text PDF PubMed Scopus (556) Google Scholar). Conversely, it has recently been shown that loss of Syk tyrosine kinase expression correlates with invasive breast carcinoma (13Coopman P.J.P. Do M.T.H. Barth M. Bowden E.T. Hayes A.J. Basyuk E. Blancato J.K. Vezza P.R. McLeskey S.W. Mangeat P.H. Mueller S.C. Nature. 2000; 406: 742-747Crossref PubMed Scopus (286) Google Scholar). Thus, although the association of ErbB overexpression with BC is compelling, its role in malignant progression is not completely understood. An alternative explanation for the strong association between BC and ErbB protein overexpression may therefore be the recent finding that ErbB2 is critical for carcinoma cell migration and invasion rather than for cell proliferation (14Spencer K.S.R. Gruas-Porter D. Leng J. Hynes N.E. Klemke R.L. J. Cell Biol. 2000; 148: 385-397Crossref PubMed Scopus (157) Google Scholar).Activated ErbB family members are tyrosine-phosphorylated and recruit signaling molecules to their intracellular domains (15Hackel P.O. Zwick E. Prenzel N. Ullrich A. Curr. Opin. Cell Biol. 1999; 11: 184-189Crossref PubMed Scopus (544) Google Scholar). As well as direct activation of Ras, phosphotidylinositol 3-kinase, and phospholipase Cγ, ErbB1 has recently been implicated in the activation of these molecules by G protein-coupled receptors (16Daub H. Wallasch C. Lankenau A. Herrlich A. Ullrich A. EMBO J. 1997; 16: 7032-7044Crossref PubMed Scopus (586) Google Scholar, 17Prenzel N. Zwick E. Daub H. Leserer M. Abraham R. Wallasch C. Ullrich A. Nature. 1999; 402: 884-888Crossref PubMed Scopus (1491) Google Scholar, 18Luttrell L.M. Daaka Y. Lefkowitz R.J. Curr. Opin. Cell Biol. 1999; 11: 177-183Crossref PubMed Scopus (603) Google Scholar). ErbB family proteins are also capable of activating, directly and indirectly, signal transducers and activators of transcription (STAT) proteins, originally identified as downstream mediators of cytokine receptor signaling (19Leonard W.J. Lin J.-X. J. Allerg. Clin. Immunol. 2000; 105: 877-888Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar). When activated by tyrosine phosphorylation, STAT proteins, of which seven have been identified, dimerize and translocate to the nucleus, where they bind to enhancer elements in cytokine-responsive gene promoters (20Horvath C.M. Darnell J.E. Curr. Opin. Cell Biol. 1997; 9: 233-239Crossref PubMed Scopus (173) Google Scholar).STAT3 appears to play critical role in the determination of cell fate (21Ihara S. Nakajima K. Fukada T. Hibi M. Nagata S. Hirano T. Fukui Y. EMBO J. 1997; 16: 5345-5352Crossref PubMed Scopus (129) Google Scholar). The differentiation of PC12 cells induced by nerve growth factor was found to require the inhibition of STAT3, implying that constitutive STAT3 activity prevents differentiation and maintains cells in a state of continual proliferation. Indeed, mouse ES cells are sustained in an undifferentiated state by activated STAT3 (22Matsuda T. Nakamura T. Nakao K. Arai T. Katsuki M. Heike T. Yokota T. EMBO J. 1999; 18: 4261-4269Crossref PubMed Scopus (718) Google Scholar). Conversely, activation of STAT3 is required for cell transformation by oncogenic Src and by a constitutively active form of Gαo, a heterotrimeric G-protein subunit (23Turkson J. Bowman T. Garcia R. Caldenhoven E., De Groot R.P. Jove R. Mol. Cell. Biol. 1998; 18: 2545-2552Crossref PubMed Scopus (590) Google Scholar, 24Ram P.T. Horvath C.M. Iyengar R. Science. 2000; 287: 142-144Crossref PubMed Scopus (95) Google Scholar). In addition, STAT3 is found to be active in fibroblasts transformed by a selection of oncoproteins and in human BC cell lines (25Sartor C.I. Dziubinski M.L. Yu C.L. Jove R. Ethier S.P. Cancer Res. 1997; 57: 978-987PubMed Google Scholar, 26Garcia R., Yu, C.-L. Hudnall A. Catlett R. Nelson K.L. Smithgall T. Fujita D.J. Ethier S.P. Jove R. Cell Growth Differ. 1997; 8: 1267-1276PubMed Google Scholar). The routes by which STAT3 is activated under these circumstances remain obscure. However, all of the data implicating STAT3 in cell transformation received further support when a form of STAT3 modified to dimerize spontaneously was shown to be oncogenic (27Bromberg J.F. Wrzeszczynska M.H. Devgan G. Zhao Y. Pestell R.G. Albanese C. Darnell J.E.J. Cell. 1999; 98: 295-303Abstract Full Text Full Text PDF PubMed Scopus (2471) Google Scholar, 28Bowman T. Garcia R. Turkson J. Jove R. Oncogene. 2000; 19: 2474-2488Crossref PubMed Scopus (1576) Google Scholar).Here we have examined a panel of six BC cell lines for ErbB and STAT protein expression and activity. We first observed marked variations in ErbB protein expression and tyrosine phosphorylation. In comparison, expression of STAT1 and STAT3 was more consistent. DNA binding assays distinguished two levels of STAT activity: acute induction of STAT·DNA complexes by EGF, which required both ErbB1 and JAK kinase activities, and a lower, serum-dependent level of STAT3 activity requiring JAK but not ErbB1 activity. Following serum withdrawal, this activity was reduced, but it was reinduced with slow kinetics following serum replacement. In contrast, conditioned medium from BC cells induced STAT3 DNA binding within minutes, suggesting the involvement of an autocrine/paracrine signaling pathway. Since proliferation of these BC cells was inhibited by dominant negative versions of STAT3 and the JAK inhibitor AG490, but not by PD153035 or PD168393, inhibitors of ErbB1 kinase activity, we infer that a serum-dependent autocrine/paracrine activation of STAT3 may be involved in BC cell proliferation.DISCUSSIONThe intended aim of these experiments was to test the notion that STAT3 activity resulting from the overexpression or constitutive activation of ErbB family proteins is a critical determinant of BC cell proliferation. However, we observed a striking variation in ErbB expression levels among the BC cell lines we compared. Moreover, the variations in expression were compounded by differences in tyrosine phosphorylation of ErbB proteins in the various cell lines. Critically, PD153035 and PD168393, which at nanomolar and micromolar concentrations, respectively, inhibit the kinase activity of ErbB1, had no effect on the proliferation of BC cells, whether the cells express (MDA-MB-468) or lack ErbB1 (BR293). Instead, we found that cell growth correlated with an elevated level of STAT3 activity, which was mediated by whole serum in part through an autocrine mechanism involving JAKs.STAT Activity as an Acute Response to EGFThe degree of STAT activation following stimulation with EGF correlated directly with the level of ErbB1 expressed in the individual BC cell lines. EGF treatment clearly stimulated tyrosine phosphorylation of STAT1 and STAT3 in BT20 and MDA-MB-468 cells within 15 min, whereas in the other cells, no increase in tyrosine phosphorylation could be discerned. In the case of MDA-MB-468 cells, this occurred in the absence of detectable ErbB2 expression, precluding the involvement of ErbB1-ErbB2 heterodimers. However, these cells express high levels of ErbB1, which may obviate a need for ErbB2. In BT20 cells, which express ErbB2 but less ErbB1 than MDA-MB-468 cells, phosphorylation of STAT1 and STAT3 resulted in a lower level of STAT DNA binding. Thus, it appears that ErbB2 expression in BT20 cells cannot compensate for lower ErbB1 expression. STAT activation by EGF was not seen in MDA-MB-231 cells (result not shown) despite detectable ErbB1 expression. BR293 cells, which lack ErbB1 expression, also showed no induction of STAT activity following EGF stimulation. Supershift assays with STAT-specific antibodies enabled the acute DNA-bound complexes in MDA-MB-468 and BT20 cells to be characterized to some extent. In line with previous observations, STAT1 and STAT3 homodimers were prominent EGF-induced complexes on the c-fos promoter element.As expected, acute STAT activation in response to EGF was dependent on the intrinsic kinase activity of ErbB1, as shown by its complete inhibition by PD153035 and PD168393. After prolonged pretreatment with PD153035 (4–6 h), even the low level of ErbB1 tyrosine phosphorylation corresponding to that seen in unstimulated cells was lost. This may reflect a gradual loss of activity by other ErbB family members as trans-phosphorylation and activation by ErbB1 is curtailed. Acute STAT activation also requires JAK kinase activity, suggesting that JAKs, and possibly STATs, may interact inducibly with ErbB1 via phosphotyrosine residues in the receptor's cytoplasmic domain. Consistent with this notion, an ErbB1 mutant with an inactive kinase domain (K721A) fails to stimulate STAT DNA binding in response to EGF. However, ErbB1 mutants that retain kinase activity but lack several tyrosine residues still stimulate STATs efficiently, 3K. Kindle, L. Li, and P. E. Shaw, unpublished data. suggesting that ErbB1 phosphorylates a substrate other than itself. This may be JAK2 or a related kinase such as JAK1 or TYK2, which could be associated either with ErbB1 independently of phosphotyrosine residues or with some other vicinal membrane protein. This, in turn, could be another receptor tyrosine kinase serving as a scaffolding protein, as has recently been proposed for the platelet-derived growth factor receptor (37Zhang Y. Turkson J. Carter-Su C. Smithgall T. Levitzki A. Kraker A. Krolewski J.J. Medveczky P. Jove R. J. Biol. Chem. 2000; 275: 24935-24944Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar).Serum-dependent STAT Activity Involving an Autocrine LoopThe STAT3-containing DNA-bound complexes observed in all BC cell lines are dependent on the presence of whole serum in the culture medium. After withdrawing serum for 18 h, its readdition led to a delayed increase in both STAT3 tyrosine phosphorylation and DNA binding. As well as differing kinetically from the acute induction by EGF, the serum-dependent STAT3 activation was unaffected by PD153035, indicating that it occurs independently of ErbB1 kinase function. However, serum activation of STAT3 was blocked by AG490, implicating JAKs in the signal pathway.Conditioned, serum-free medium from BR293 (Fig. 7) or MDA-MB-468 cells (not shown) stimulated with 10% FCS for 2 h induced STAT3·DNA complexes in BR293 cells within 15 min. This observation provides compelling evidence for the involvement of an autocrine/paracrine loop in the delayed activation of STAT3 DNA binding by serum. Moreover, we found that JAK2 becomes phosphorylated upon serum stimulation and that AG490 inhibited the delayed response to serum but not the rapid response to conditioned medium, suggesting that JAKs mediate the production of autocrine factors by cells but not the cells' response to them.Several instances of JAK/STAT activation by autocrine mechanisms have been described to date. For example, in rat cardiomyocytes, angiotensin II has been shown to cause the delayed activation of STAT3 via the secretion of interleukin-6 family cytokines (38Kodama H. Fukuda K. Pan J. Makino S. Sano M. Takahashi T. Hori S. Ogawa S. Circ. Res. 1998; 82: 244-250Crossref PubMed Scopus (92) Google Scholar, 39Sano M. Fukuda K. Kodama H. Takahashi T. Kato T. Hakuno D. Sato T. Manabe T. Tahara S. Ogawa S. Biochem. Biophys. Res. Commun. 2000; 269: 798-802Crossref PubMed Scopus (51) Google Scholar). Moreover, the autocrine secretion of prolactin by BC cells has been shown to cause tyrosine phosphorylation and activation of both ErbB2 and JAK2 (40Yamauchi T. Yamauchi N. Ueki K. Sugiyama T. Waki H. Miki H. Tobe K. Matsuda S. Tsushima T. Yamamoto T. Fujita T. Taketani Y. Fukayama M. Kimura S. Yazaki Y. Nagai R. Kadowaki T. J. Biol. Chem. 2000; 275: 33937-33944Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar). The autocrine pathway we describe appears not to correspond to either of the above. First, we fail to detect tyrosine phosphorylation of gp130, the signaling chain common to interleukin-6 family receptors, suggesting that interleukin-6-type cytokines are not involved. 4L. Li and P. E. Shaw, unpublished data. Second, JAKs are implicated here in the release of autocrine factors rather than in the cells' subsequent response to them. We are currently characterizing the pathway further with a range of specific molecular inhibitors.Autocrine Activation of STATs Linked to BC Cell ProliferationGiven that STAT3 activity has been linked to cell proliferation in several contexts (41Ni Z. Lou W. Leman E.S. Gao A.C. Cancer Res. 2000; 60: 1225-1228PubMed Google Scholar, 42De Vos J. Jourdan M. Tarte K. Jasmin C. Klein B. Br. J. Haematol. 2000; 109: 823-828Crossref PubMed Scopus (160) Google Scholar), the finding that the overexpression of dominant negative STAT3 alleles in BC cell lines reduces proliferation was not unprecedented. In these assays, in which transiently transfected cells were selected on the basis of GFP co-expression, cell proliferation, as measured by [3H]thymidine incorporation, was inhibited by expression of dominant negative STAT3 proteins but not by the wild type protein. The STAT3 Y/F mutant lacks the tyrosine residue involved in dimer formation and may block STAT3 activation by forming nonproductive complexes with activated receptors and kinases. The STAT3 E/V mutant fails to bind DNA (24Ram P.T. Horvath C.M. Iyengar R. Science. 2000; 287: 142-144Crossref PubMed Scopus (95) Google Scholar). The degree of growth inhibition observed was reproducible and statistically significant. Thus, both inhibitory STAT3 mutants suppress the growth of those cells in which they are expressed.As discussed above, ErbB proteins have also been implicated in BC proliferation, but in contrast to dominant-negative STAT3 proteins, PD153035 and PD168393, which at the concentrations used specifically inhibit ErbB1 kinase activity, failed to suppress BC cell growth. Although we cannot rule out that other ErbB proteins may play a role in driving proliferation, our results do imply that the pronounced expression of ErbB1 in MDA-MB-468 or BT20 cells is unlikely to be a critical factor for their proliferation. This would be in line with the conclusions of others that ErbB proteins influence cell invasion and the metastatic potential of malignant BC cells (14Spencer K.S.R. Gruas-Porter D. Leng J. Hynes N.E. Klemke R.L. J. Cell Biol. 2000; 148: 385-397Crossref PubMed Scopus (157) Google Scholar).Our findings that AG490 strongly inhibits BC cell growth and serum-dependent, elevated STAT3 activity link the STAT3-dependent BC cell proliferation to an autocrine signaling pathway activated by serum factors. Also consistent with this notion is the observation that MCF-10F nontumorigenic breast epithelial cells are clearly less susceptible to growth inhibition by AG490. The explanation for this may be the absence of STAT3 phosphorylation and DNA binding activity in these cells, as shown here and reported previously (26Garcia R., Yu, C.-L. Hudnall A. Catlett R. Nelson K.L. Smithgall T. Fujita D.J. Ethier S.P. Jove R. Cell Growth Differ. 1997; 8: 1267-1276PubMed Google Scholar). While this manuscript was under revision, another study was published demonstrating the ability of AG490 to block the growth of BC cell lines with constitutive STAT3 activity (43Garcia R. Bowman T.L. Niu G., Yu, H. Minton S. Muro-Cacho C.A. Cox C.E. Falcone R. Fairclough R. Parsons S. Laudano A. Gazit A. Levitzki A. Kraker A. Jove R. Oncogene. 2001; 20: 2499-2513Crossref PubMed Scopus (649) Google Scholar). AG490 was first described as a suppressor of leukemic cell growth via its inhibitory effects on JAKs and has been shown to inhibit STATs and suppress the growth of other cancer cells (41Ni Z. Lou W. Leman E.S. Gao A.C. Cancer Res. 2000; 60: 1225-1228PubMed Google Scholar, 42De Vos J. Jourdan M. Tarte K. Jasmin C. Klein B. Br. J. Haematol. 2000; 109: 823-828Crossref PubMed Scopus (160) Google Scholar). In our hands, AG490 inhibited the delayed induction of STAT·DNA complexes by serum but failed to have an impact on the rapid response elicited by conditioned medium. This suggests that it is the initial expression of a stimulatory factor or its release from cells that requires JAK function rather than the response to its presence in conditioned medium. The release of autocrine factors may therefore constitute one pathway by which BC cells maintain STAT3 activity and consequently their own proliferation. The mitogenic potential of ErbB family members has been implicated in the genesis of a variety of human carcinomas, and in the majority of BC cases, overexpression of ErbB proteins is detected. The epidermal growth factor receptor (ErbB1) is found overexpressed in some cancers, as is ErbB3, and ErbB1 has been shown to be tumorigenic in murine fibroblasts when overexpressed, but notably, only when activated by ligand (1Velu T.J. Beguinot L. Vass W.C. Willingham M.C. Merlino G.T. Pastan I. Lowy D.R. Science. 1987; 238: 1408-1410Crossref PubMed Scopus (350) Google Scholar). ErbB2 is overexpressed in a wide range of human tumors as a result of gene amplification or transcriptional activation. Thirty percent of invasive breast carcinomas overexpress ErbB2, and this correlates with a poor prognosis (2Lupu R. Cardillo M. Harris L. Hijazi M. Rosenberg K. Semin. Cancer Biol. 1995; 6: 135-145Crossref PubMed Scopus (57) Google Scholar). Indeed, ErbB2 is the only member of the ErbB family for which no ligand has been identified and the only receptor tyrosine kinase that, in the absence of ligand, appears to cause transformation when overexpressed in NIH3T3 cells (3Hynes N.E. Stern D.F. Biochim. Biophys. Acta. 1994; 1198: 165-184Crossref PubMed Scopus (998) Google Scholar, 4Difiore P.P. Pierce J.H. Kraus M.H. Segatto O. King C.R. Aaronson S.A. Science. 1987; 237: 178-182Crossref PubMed Scopus (861) Google Scholar, 5Hudziak R.M. Schlessinger J. Ullrich A. Proc. Natl. Acad. Sci. U. S. A. 1987; 84: 7159-7163Crossref PubMed Scopus (548) Google Scholar). The link between ErbB2 and oncogenesis has therefore been the subject of much consideration. Overexpression of ErbB2 is sufficient to cause its hyperphosphorylation, which may trigger signaling and transformation (6Stern D.F. Kamps M.P. Cao H. Mol. Cell. Biol. 1988; 8: 3969-3973Crossref PubMed Scopus (125) Google Scholar). Alternatively, ErbB2 overexpression may enhance the binding affinities of both EGF 1The abbreviations used are: EGFepidermal growth factorSTATsignal transducers and activators of transcriptionJAKJanus kinaseEMSAelectrophoretic mobility shift assayPVDFpolyvinylidene difluoridePBSphosphate-buffered salineFCSfetal calf serumSIEv-Sis-inducible elementGFPgreen fluorescent protein 1The abbreviations used are: EGFepidermal growth factorSTATsignal transducers and activators of transcriptionJAKJanus kinaseEMSAelectrophoretic mobility shift assayPVDFpolyvinylidene difluoridePBSphosphate-buffered salineFCSfetal calf serumSIEv-Sis-inducible elementGFPgreen fluorescent protein and neu differentiation factor for their ligands, thereby amplifying subsequent downstream signals. Thus, ErbB2 overexpression may allow tumor cells to respond to low concentrations of mitogenic growth factors (7Karunagaran D. Tzahar E. Beerli R.R. Chen X. Graus-Porta D. Ratzkin B.J. Seger R. Hynes N.E. Yarden Y. EMBO J. 1996; 15: 254-264Crossref PubMed Scopus (585) Google Scholar). However, in vitro assays indicate that although low levels of neu differentiation factor increase the growth rate of cancer cell lines overexpressing ErbB2, higher levels result in anti-proliferative and differentiating effects (2Lupu R. Cardillo M. Harris L. Hijazi M. Rosenberg K. Semin. Cancer Biol. 1995; 6: 135-145Crossref PubMed Scopus (57) Google Scholar). epidermal growth factor signal transducers and activators of transcription Janus kinase electrophoretic mobility shift assay polyvinylidene difluoride phosphate-buffered saline fetal calf serum v-Sis-inducible element green fluorescent protein epidermal growth factor signal transducers and activators of transcription Janus kinase electrophoretic mobility shift assay polyvinylidene difluoride phosphate-buffered saline fetal calf serum v-Sis-inducible element green fluorescent protein Analyses of transgenic mice carrying ErbB2 have indicated that its overexpression alone is insufficient to cause malignancies, since those detected could be attributed to somatic activating mutations in the extracellular domain of ErbB2 (8Siegel P.M. Dankort D.L. Hardy W.R. Muller W.J. Mol. Cell. Biol. 1994; 14: 7068-7077Crossref PubMed Scopus (187) Google Scholar). Subsequent work revealed a splice variant of ErbB2 in human BC samples with in vitro transforming potential (9Siegel P.M. Ryan E.D. Cardiff R.D. Muller W.J. EMBO J. 1999; 18: 2149-2164Crossref PubMed Scopus (369) Google Scholar). However, other factors may contribute to tumorigenesis mediated by ErbB overexpression. For example, c-Src, which is also overexpressed in BC (10Ottenhoff-Kalff A.E. Rijksen G. van Beurden E.A.C.M. Hennipman A. Michels A.A. Staal G.E.J. Cancer Res. 1992; 52: 4773-4778PubMed Google Scholar), is able to synergize with ErbB1 to transform cells (11Tice D.A. Biscardi J.S. Nickles A.L. Parsons S.J. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 1415-1420Crossref PubMed Scopus (397) Google Scholar), possibly by c-Src-mediated receptor phosphorylation (12Biscardi J.S. Maa M.-C. Tice D.A. Cox M.E. Leu T.-H. Parsons S.J. J. Biol. Chem. 1999; 274: 8335-8343Abstract Full Text Full Text PDF PubMed Scopus (556) Google Scholar). Conversely, it has recently been shown that loss of Syk tyrosine kinase expression correlates with invasive breast carcinoma (13Coopman P.J.P. Do M.T.H. Barth M. Bowden E.T. Hayes A.J. Basyuk E. Blancato J.K. Vezza P.R. McLeskey S.W. Mangeat P.H. Mueller S.C. Nature. 2000; 406: 742-747Crossref PubMed Scopus (286) Google Scholar). Thus, although the association of ErbB overexpression with BC is compelling, its role in malignant progression is not completely understood. An alternative explanation for the strong association between BC and ErbB protein overexpression may therefore be the recent finding that ErbB2 is critical for carcinoma cell migration and invasion rather than for cell proliferation (14Spencer K.S.R. Gruas-Porter D. Leng J. Hynes N.E. Klemke R.L. J. Cell Biol. 2000; 148: 385-397Crossref PubMed Scopus (157) Google Scholar). Activated ErbB family members are tyrosine-phosphorylated and recruit signaling molecules to their intracellular domains (15Hackel P.O. Zwick E. Prenzel N. Ullrich A. Curr. Opin. Cell Biol. 1999; 11: 184-189Crossref PubMed Scopus (544) Google Scholar). As well as direct activation of Ras, phosphotidylinositol 3-kinase, and phospholipase Cγ, ErbB1 has recently been implicated in the activation of th" @default.
• W2046604039 created "2016-06-24" @default.
• W2046604039 creator A5027475930 @default.
• W2046604039 creator A5070563271 @default.
• W2046604039 date "2002-05-01" @default.
• W2046604039 modified "2023-10-10" @default.
• W2046604039 title "Autocrine-mediated Activation of STAT3 Correlates with Cell Proliferation in Breast Carcinoma Lines" @default.
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