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Possible role of Stat5a in rat mammary gland carcinogenesis

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Abstract

Signal transducer and activator of transcription (Stat) 5a is a transcription factor mediating the action of specific cytokines, growth factors and hormones on gene expression. In the mammary gland, Stat5a is well recognized for its function in prolactin signaling, lobuloalveolar development, and milk protein expression during pregnancy and lactation. Latent cytoplasmic Stat5a is activated by tyrosine phosphorylation and following dimerization undergoes nuclear import. In the current study, Stat5a expression was examined immunohistochemically in carcinomas induced by the chemical carcinogens 7,12-dimethylbenz[a]anthracene and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine. A high percentage of carcinomas showed nuclear labeling of Stat5a [44 of 68 (65%)] with Stat5a nuclear labeling index ranging from 18 to 77%. In contrast, control normal mammary gland tissue displayed cytosolic expression. Carcinomas with different Stat5a staining patterns (cytoplasmic or nuclear) showed a statistical difference for the proliferating cell nuclear antigen (PCNA) labeling, tumor differentiation, nuclear grade, mitotic activity, and tumor size. High Stat5a nuclear expression was closely correlated with the higher-grade carcinomas. Stat5a nuclear expression was also detected in intraductal proliferations (10 of 21 lesions) and in ductal carcinomas in situ (13 of 15 lesions). Immunohistochemical analysis was further carried out in human breast cancers. Stat5a nuclear expression was detected in ductal and lobular carcinomas and DCIS at a frequency of 48% (15/31), 33% (2/6), and 40% (2/5), respectively. Nuclear expression of Stat5a in human breast cancers also correlated with the PCNA nuclear labeling index. The findings implicate activated Stat5a in mammary gland cancer development in the rat and human.

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References

  • R Buettner LB Mora R Jove (2002) ArticleTitleActivated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention Clin Cancer Res 8 945–954

    Google Scholar 

  • V Calò M Migliavacca V Bazan M Macaluso M Buscemi N Gebbia A Russo (2003) ArticleTitleSTAT proteins: from normal control of cellular events to tumorigenesis J Cell Physiol 197 157–168

    Google Scholar 

  • J Bromberg (2002) ArticleTitleStat proteins and oncogenesis J Clin Invest 109 1139–1142

    Google Scholar 

  • H Yu R Jove (2004) ArticleTitleThe stats of cancer- new molecular targets come of age Nature Rev 4 97–105

    Google Scholar 

  • DE Levy JE Darnell (2002) ArticleTitleStats: transcriptional control and biological impact Nature Rev Mol Cell Biol 3 651–662

    Google Scholar 

  • AV Kazansky B Raught SM Lindsey Y Wang JM Rosen (1995) ArticleTitleRegulation of mammary gland factor/Stat5a during mammary gland development Mol Endocrinol 9 1598–1609

    Google Scholar 

  • Z Liu GW Robinson L Henninghausen (1996) ArticleTitleActivation of Stat5a and Stat5b by tyrosine phosphorylation is tightly linked to mammary gland differentiation Mol Endocrinol 10 1496–1506

    Google Scholar 

  • X Liu GW Robinson K-U Wagner L Garrett A Wynshaw-Boris L Henninghausen (1997) ArticleTitleStat5a is mandatory for adult mammary gland development and lactogenesis Genes Develop 11 179–186

    Google Scholar 

  • RC Humphreys L Henninghausen (1999) ArticleTitleSignal transducer and activator of transcription 5a influences mammary epithelial cell survival and tumorigenesis Cell Growth Diff 10 685–694

    Google Scholar 

  • K Miyoshi JM Shillingford GH Smith SI Grimm K-U Wagner T Oka JM Rosen GW Robinson L Henninghausen (2001) ArticleTitleSignal transducer and activator of transcription (Stat) 5 controls the proliferation and differentiation of mammary alveolar epithelium J Cell Biol 155 531–542

    Google Scholar 

  • JL Brockman MD Schroeder LA Schuler (2002) ArticleTitlePRL activates the cyclic D1 promoter via the Jak2/Stat pathway Mol Endocrinol 16 774–784

    Google Scholar 

  • BN Friedrichsen HE Richter JA Hansen CJ Rhodes JH Nielsen N Billestrup A Møldrup (2003) ArticleTitleSignal transducer and activator of transcription 5 activation is sufficient to drive transcriptional induction of cyclic D2 gene and proliferation of rat pancreatic β-cells Mol Endocrinol 17 945–968

    Google Scholar 

  • RP Groot Particlede JA Raaijmakers JW Lammers R Jove L Koenderman (1999) ArticleTitleSTAT5 activation by BCR-Abl contributes to transformation of K562 leukemia cells Blood 94 1108–1112

    Google Scholar 

  • S Ren HR Cai M Li PA Furth (2002) ArticleTitleLoss of Stat5a delays mammary cancer progression in a mouse model Oncogene 21 4335–4339

    Google Scholar 

  • J-R Hsiao Y-T Jin S-T Tsai A-L Shiau C-L Wu W-C Su (2003) ArticleTitleConstitutive activation of STAT3 and STAT5 is present in the majority of nasopharyngeal carcinoma and correlates with better prognosis Brit J Cancer 89 344–349

    Google Scholar 

  • CJ Watson WR Miller (1995) ArticleTitleElevated levels of members of the STAT family of transcription factors in breast carcinoma nuclear extracts Brit J Cancer 71 840–844

    Google Scholar 

  • I Cotarla S Ren Y Zhang E Gehan B Singh PA Furth (2004) ArticleTitleStat5a is tyrosine phosphorylated and nuclear localized in a high proportion of human breast cancers Int J Cancer 108 665–671

    Google Scholar 

  • J Russo BA Gusterson AE Rogers IH Russo SR Wellings MJ Zwieten Particlevan (1990) ArticleTitleBiology of disease Comparative study of human and rat mammary tumorigenesis. Lab Invest 62 244–278

    Google Scholar 

  • L Shan M He M Yu C Qiu NH Lee ET Liu EG Snyderwine (2002) ArticleTitlecDNA microarray profiling of rat mammary gland carcinomas induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and 7,12-dimethylbenz[a]anthracene Carcinogenesis 23 1561–1568

    Google Scholar 

  • A Ghoshal KH Preisegger S Takayama SS Thorgeirsson EG Snyderwine (1994) ArticleTitleInduction of mammary tumors in female Sprague–Dawley rats by the food-derived carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and effect of dietary fat Carcinogenesis 15 2429–2433

    Google Scholar 

  • EG Snyderwine UP Thorgeirsson M Venugopal SJ Robert-Thomson (1998) ArticleTitleMammary gland carcinogenicity of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in Sprague–Dawley rats on high- and low-fat diets Nutr Cancer 31 160–167

    Google Scholar 

  • M Yu EG Snyderwine (2002) ArticleTitleH-ras oncogene mutations during development of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced rat mammary gland cancer Carcinogenesis 23 2123–2128

    Google Scholar 

  • I Costa M Solanas E Escrich (2002) ArticleTitleHistopathologic characterization of mammary neoplastic lesions induced with 7,12-dimethylbenz(α)anthracene in the rat Arch Pathol Lab Med 126 915–927

    Google Scholar 

  • SJ Roberts-Thomson EG Snyderwine (1998) ArticleTitlemRNA differential display of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine-induced rat mammary gland tumors Breast Cancer Res Treat 51 99–107

    Google Scholar 

  • C Qiu L Shan M Yu EG Snyderwine (2003) ArticleTitleDeregulation of the cyclic D1/Cdk4 retinoblastoma pathway in rat mammary gland carcinomas induced by the food-derived carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine Cancer Res 63 5674–5678

    Google Scholar 

  • TJ Jang MS Kang H Kim DH Kim JI Lee JR Kim (2000) ArticleTitleIncreased expression of cyclic D1, cyclic E and p21(Cip1) associated with decreased expression of p27(Kip1) in chemically induced rat mammary carcinogenesis Japan J Cancer Res 91 1222–1232

    Google Scholar 

  • A Alkarain J Slingerland (2004) ArticleTitleDeregulation of p27 by oncogenic signaling and its prognostic significance in breast cancer Breast Cancer Res 6 13–21

    Google Scholar 

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Authors and Affiliations

  1. Chemical Carcinogenesis Section, Laboratory of Experimental Carcinogenesis, CCR, NCI, Building 37, Room 4146, 37 Convent Dr., Bethesda, MD, 20892-4262, USA

    Liang Shan, Minshu Yu & Elizabeth G. Snyderwine

  2. Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

    Bradly D. Clark

Authors
  1. Liang Shan
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  2. Minshu Yu
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  3. Bradly D. Clark
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  4. Elizabeth G. Snyderwine
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Correspondence to Elizabeth G. Snyderwine.

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Shan, L., Yu, M., Clark, B.D. et al. Possible role of Stat5a in rat mammary gland carcinogenesis. Breast Cancer Res Treat 88, 263–272 (2004). https://doi.org/10.1007/s10549-004-0805-2

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