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Janus kinase 2 is required for the initiation but not maintenance of prolactin-induced mammary cancer

Oncogene volume 29, pages 5359–5369 (2010)Cite this article

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Abstract

The prolactin receptor (PRLR), its associated Janus kinase 2 (Jak2) and the signal transducer and activator of transcription 5 (Stat5) are essential for normal mammary gland development. Owing to the upregulation of the PRLR and the local synthesis of its ligand in neoplastic cells, it has been proposed that PRL can act as a local growth factor in human breast cancers. This notion is supported by experimental evidence in transgenic mice, which showed that the mammary-specific expression of PRL contributes to carcinogenesis in vivo. To assess the importance of Jak2/Stat5 signaling during mammary cancer initiation and progression, we generated a PRL-induced mammary cancer model that allows the functional ablation of the Jak2 gene in the mammary epithelium before and after neoplastic transformation. Collectively, the results of this study show that the functional ablation of Jak2 protects against the onset of PRL-induced mammary tumorigenesis, suggesting that targeting this kinase is a relevant strategy for mammary cancer prevention. Surprisingly, Jak2 deficiency did not affect the growth and survival of PRL-induced mammary cancer cells in culture and in vivo. Consequently, Jak2 cannot be a sole therapeutic target to treat the established disease. PRL-induced mammary cancers exhibited an upregulation of ErbB2 and other ErbB receptor tyrosine kinases that may supersede the functionality of PRLR signaling through Jak2.

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References

  • Aoui-Jamali MA, Song DJ, Benlimame N, Yen L, Deng X, Hernandez-Perez M et al. (2003). Regulation of multiple tumor microenvironment markers by overexpression of single or paired combinations of ErbB receptors. Cancer Res 63: 3764–3774.

    Google Scholar 

  • Arendt LM, Rose-Hellekant TA, Sandgren EP, Schuler LA . (2006). Prolactin potentiates transforming growth factor alpha induction of mammary neoplasia in transgenic mice. Am J Pathol 168: 1365–1374.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Arendt LM, Schuler LA . (2008). Prolactin drives estrogen receptor-alpha-dependent ductal expansion and synergizes with transforming growth factor-alpha to induce mammary tumors in males. Am J Pathol 172: 194–202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Boulanger CA, Wagner KU, Smith GH . (2005). Parity-induced mouse mammary epithelial cells are pluripotent, self-renewing and sensitive to TGF-beta1 expression. Oncogene 24: 552–560.

    Article  CAS  PubMed  Google Scholar 

  • Brockman JL, Schroeder MD, Schuler LA . (2002). PRL activates the cyclin D1 promoter via the Jak2/Stat pathway. Mol Endocrinol 16: 774–784.

    Article  CAS  PubMed  Google Scholar 

  • Brockman JL, Schuler LA . (2005). Prolactin signals via Stat5 and Oct-1 to the proximal cyclin D1 promoter. Mol Cell Endocrinol 239: 45–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cardiff RD . (1998). Are the TDLU of the human the same as the LA of mice? J Mammary Gland Biol Neoplasia 3: 3–5.

    Article  CAS  PubMed  Google Scholar 

  • Clevenger CV, Chang WP, Ngo W, Pasha TL, Montone KT, Tomaszewski JE . (1995). Expression of prolactin and prolactin receptor in human breast carcinoma. Evidence for an autocrine/paracrine loop. Am J Pathol 146: 695–705.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cotarla I, Ren S, Zhang Y, Gehan E, Singh B, Furth PA . (2004). Stat5a is tyrosine phosphorylated and nuclear localized in a high proportion of human breast cancers. Int J Cancer 108: 665–671.

    Article  CAS  PubMed  Google Scholar 

  • Cui Y, Riedlinger G, Miyoshi K, Tang W, Li C, Deng CX et al. (2004). Inactivation of Stat5 in mouse mammary epithelium during pregnancy reveals distinct functions in cell proliferation, survival, and differentiation. Mol Cell Biol 24: 8037–8047.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Diehl JA, Cheng M, Roussel MF, Sherr CJ . (1998). Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. Genes Dev 12: 3499–3511.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dominguez-Caceres MA, Garcia-Martinez JM, Calcabrini A, Gonzalez L, Porque PG, Leon J et al. (2004). Prolactin induces c-Myc expression and cell survival through activation of Src/Akt pathway in lymphoid cells. Oncogene 23: 7378–7390.

    Article  CAS  PubMed  Google Scholar 

  • Garcia-Martinez JM, Calcabrini A, Gonzalez L, Martin-Forero E, gullo-Ortuno MT, Simon V et al. (2010). A non-catalytic function of the Src family tyrosine kinases controls prolactin-induced Jak2 signaling. Cell Signal 22: 415–426.

    Article  CAS  PubMed  Google Scholar 

  • Ginsburg E, Vonderhaar BK . (1995). Prolactin synthesis and secretion by human breast cancer cells. Cancer Res 55: 2591–2595.

    CAS  PubMed  Google Scholar 

  • Hankinson SE, Willett WC, Michaud DS, Manson JE, Colditz GA, Longcope C et al. (1999). Plasma prolactin levels and subsequent risk of breast cancer in postmenopausal women. J Natl Cancer Inst 91: 629–634.

    Article  CAS  PubMed  Google Scholar 

  • Henry MD, Triplett AA, Oh KB, Smith GH, Wagner KU . (2004). Parity-induced mammary epithelial cells facilitate tumorigenesis in MMTV-neu transgenic mice. Oncogene 23: 6980–6985.

    Article  CAS  PubMed  Google Scholar 

  • Holbro T, Beerli RR, Maurer F, Koziczak M, Barbas CF, Hynes NE . (2003). The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation. Proc Natl Acad Sci USA 100: 8933–8938.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Horseman ND, Zhao W, Montecino-Rodriguez E, Tanaka M, Nakashima K, Engle SJ et al. (1997). Defective mammopoiesis, but normal hematopoiesis, in mice with a targeted disruption of the prolactin gene. EMBO J 16: 6926–6935.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Humphreys RC, Hennighausen L . (1999). Signal transducer and activator of transcription 5a influences mammary epithelial cell survival and tumorigenesis. Cell Growth Differ 10: 685–694.

    CAS  PubMed  Google Scholar 

  • Iavnilovitch E, Cardiff RD, Groner B, Barash I . (2004). Deregulation of Stat5 expression and activation causes mammary tumors in transgenic mice. Int J Cancer 112: 607–619.

    Article  CAS  PubMed  Google Scholar 

  • Iavnilovitch E, Groner B, Barash I . (2002). Overexpression and forced activation of stat5 in mammary gland of transgenic mice promotes cellular proliferation, enhances differentiation, and delays postlactational apoptosis. Mol Cancer Res 1: 32–47.

    CAS  PubMed  Google Scholar 

  • Kim A, Liu B, Ordonez-Ercan D, Alvarez K, Jones L, McKimmey C et al. (2005). Functional interaction between mouse erbB3 and wild-type rat c-neu in transgenic mouse mammary tumor cells. Breast Cancer Res 7: R708–R718.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Krempler A, Qi Y, Triplett AA, Zhu J, Rui H, Wagner KU . (2004). Generation of a conditional knockout allele for the Janus kinase 2 (Jak2) gene in mice. Genesis 40: 52–57.

    Article  CAS  PubMed  Google Scholar 

  • Lim E, Vaillant F, Wu D, Forrest NC, Pal B, Hart AH et al. (2009). Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers. Nat Med 15: 907–913.

    Article  CAS  PubMed  Google Scholar 

  • Matulka LA, Triplett AA, Wagner KU . (2007). Parity-induced mammary epithelial cells are multipotent and express cell surface markers associated with stem cells. Dev Biol 303: 29–44.

    Article  CAS  PubMed  Google Scholar 

  • Matulka LA, Wagner KU . (2005). Models of Breast Cancer. Drug Discov Today Dis Models 2: 1–6.

    Article  CAS  Google Scholar 

  • Medina D, Kittrell FS . (2000). Establishment of mouse mammary cell lines. In: Ip MM, Ash BB (eds). Methods in Mammary Gland Biology and Breast Cancer, chapter 13. Kluwer Academic/Plenum Publishers: New York. pp 137–145.

    Chapter  Google Scholar 

  • Miermont AM, Parrish AR, Furth PA . (2010). Role of ERα in the differential response of Stat5a loss in susceptibility to mammary preneoplasia and DMBA-induced carcinogenesis. Carcinogenesis 31: 1124–1131.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nevalainen MT, Xie J, Torhorst J, Bubendorf L, Haas P, Kononen J et al. (2004). Signal transducer and activator of transcription-5 activation and breast cancer prognosis. J Clin Oncol 22: 2053–2060.

    Article  CAS  PubMed  Google Scholar 

  • Oakes SR, Robertson FG, Kench JG, Gardiner-Garden M, Wand MP, Green JE et al. (2007). Loss of mammary epithelial prolactin receptor delays tumor formation by reducing cell proliferation in low-grade preinvasive lesions. Oncogene 26: 543–553.

    Article  CAS  PubMed  Google Scholar 

  • Ormandy CJ, Camus A, Barra J, Damotte D, Lucas B, Buteau H et al. (1997). Null mutation of the prolactin receptor gene produces multiple reproductive defects in the mouse. Genes Dev 11: 167–178.

    Article  CAS  PubMed  Google Scholar 

  • Pardanani A . (2007). JAK2 inhibitor therapy in myeloproliferative disorders: rationale, preclinical studies and ongoing clinical trials. Leukemia 22: 23–30.

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Rose-Hellekant TA, Arendt LM, Schroeder MD, Gilchrist K, Sandgren EP, Schuler LA . (2003). Prolactin induces ERalpha-positive and ERalpha-negative mammary cancer in transgenic mice. Oncogene 22: 4664–4674.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sakamoto K, Creamer BA, Triplett AA, Wagner KU . (2007). The Janus kinase 2 is required for expression and nuclear accumulation of cyclin D1 in proliferating mammary epithelial cells. Mol Endocrinol 21: 1877–1892.

    Article  CAS  PubMed  Google Scholar 

  • Sakamoto K, Lin WC, Triplett AA, Wagner KU . (2009). Targeting janus kinase 2 in Her2/neu-expressing mammary cancer: Implications for cancer prevention and therapy. Cancer Res 69: 6642–6650.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shillingford JM, Miyoshi K, Robinson GW, Grimm SL, Rosen JM, Neubauer H et al. (2002). Jak2 is an essential tyrosine kinase involved in pregnancy-mediated development of mammary secretory epithelium. Mol Endocrinol 16: 563–570.

    Article  CAS  PubMed  Google Scholar 

  • Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE et al. (1989). Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244: 707–712.

    Article  CAS  PubMed  Google Scholar 

  • Tang JZ, Zuo ZH, Kong XJ, Steiner M, Yin Z, Perry JK et al. (2010). Signal transducer and activator of transcription (STAT)-5A and STAT5B differentially regulate human mammary carcinoma cell behavior. Endocrinology 151: 43–55.

    Article  CAS  PubMed  Google Scholar 

  • Teglund S, McKay C, Schuetz E, van Deursen JM, Stravopodis D, Wang D et al. (1998). Stat5a and Stat5b proteins have essential and nonessential, or redundant, roles in cytokine responses. Cell 93: 841–850.

    Article  CAS  PubMed  Google Scholar 

  • Tornell J, Rymo L, Isaksson OG . (1991). Induction of mammary adenocarcinomas in metallothionein promoter-human growth hormone transgenic mice. Int J Cancer 49: 114–117.

    Article  CAS  PubMed  Google Scholar 

  • Tran TH, Utama FE, Lin J, Yang N, Sjolund AB, Ryder A et al. (2010). Prolactin inhibits BCL6 expression in breast cancer through a Stat5a-dependent mechanism. Cancer Res 70: 1711–1721.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Triplett AA, Montagna C, Wagner KU . (2008). A mammary-specific, long-range deletion on mouse chromosome 11 accelerates Brca1-associated mammary tumorigenesis. Neoplasia 10: 1325–1334.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tworoger SS, Hankinson SE . (2006). Prolactin and breast cancer risk. Cancer Lett 243: 160–169.

    Article  CAS  PubMed  Google Scholar 

  • Wagner KU, Boulanger CA, Henry MD, Sgagias M, Hennighausen L, Smith GH . (2002). An adjunct mammary epithelial cell population in parous females: its role in functional adaptation and tissue renewal. Development 129: 1377–1386.

    CAS  PubMed  Google Scholar 

  • Wagner KU, Krempler A, Triplett AA, Qi Y, George NM, Zhu J et al. (2004). Impaired alveologenesis and maintenance of secretory mammary epithelial cells in Jak2 conditional knockout mice. Mol Cell Biol 24: 5510–5520.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wagner KU, McAllister K, Ward T, Davis B, Wiseman R, Hennighausen L . (2001). Spatial and temporal expression of the Cre gene under the control of the MMTV-LTR in different lines of transgenic mice. Transgenic Res 10: 545–553.

    Article  CAS  PubMed  Google Scholar 

  • Wagner KU, Rui H . (2008). Jak2/Stat5 signaling in mammogenesis, breast cancer initiation and progression. J Mammary Gland Biol Neoplasia 13: 93–103.

    Article  PubMed  Google Scholar 

  • Wagner KU, Wall RJ, St-Onge L, Gruss P, Wynshaw-Boris A, Garrett L et al. (1997a). Cre-mediated gene deletion in the mammary gland. Nucleic Acids Res 25: 4323–4330.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wagner KU, Young III WS, Liu X, Ginns EI, Li M, Furth PA et al. (1997b). Oxytocin and milk removal are required for post-partum mammary-gland development. Genes Funct 1: 233–244.

    Article  CAS  PubMed  Google Scholar 

  • Wellings SR, Jensen HM, Marcum RG . (1975). An atlas of subgross pathology of the human breast with special reference to possible precancerous lesions. J Natl Cancer Inst 55: 231–273.

    CAS  PubMed  Google Scholar 

  • Wennbo H, Gebre-Medhin M, Gritli-Linde A, Ohlsson C, Isaksson OG, Tornell J . (1997). Activation of the prolactin receptor but not the growth hormone receptor is important for induction of mammary tumors in transgenic mice. J Clin Invest 100: 2744–2751.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by the Public Health Service Grant CA117930 (to K-UW) as well as Grant CA78312 (to LAS) from the National Cancer Institute. Additional financial support provided to K-UW by the Nebraska Cancer and Smoking Disease Research Program (NE DHHS LB506 2009-45) was imperative to finance the maintenance of the Jak2 conditional knockout model. KS received a postdoctoral fellowship from the Susan G Komen Breast Cancer Foundation (PDF0600835).

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Authors and Affiliations

  1. Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA

    K Sakamoto, A A Triplett & K-U Wagner

  2. Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI, USA

    L A Schuler

  3. Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA

    K-U Wagner

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  1. K Sakamoto
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Correspondence to K-U Wagner.

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Sakamoto, K., Triplett, A., Schuler, L. et al. Janus kinase 2 is required for the initiation but not maintenance of prolactin-induced mammary cancer. Oncogene 29, 5359–5369 (2010). https://doi.org/10.1038/onc.2010.274

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