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Targeting Janus Kinase 2 in Her2/Neu-Expressing Mammary Cancer: Implications for Cancer Prevention Andtherapy

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Targeting Janus Kinase 2 in Her2/Neu-Expressing Mammary Cancer: Implications for Cancer Prevention Andtherapy Published OnlineFirst July 28, 2009; DOI: 10.1158/0008-5472.CAN-09-0746 Molecular Biology, Pathobiology, andGenetics Targeting Janus Kinase 2 in Her2/neu-Expressing Mammary Cancer: Implications for Cancer Prevention andTherapy Kazuhito Sakamoto,1 Wan-chi Lin,1 Aleata A. Triplett,1 and Kay-Uwe Wagner1,2 1Eppley Institute for Research in Cancer and Allied Diseases and 2Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska Abstract the Stat5-mediated transcriptional activation of the cyclin D1 The Janus kinase 2 (Jak2) is essential for normal mammary promoter (5). Our own studies using Jak2-deficient mammary gland development, but this tyrosine kinase and its main epithelial cells and their isogenic wild-type controls suggest that effector, signal transducer and activator of transcription 5, are signaling through this Janus kinase controls not only the also active in a significant subset of human breast cancers. We expression of the cyclin D1 mRNA but, more importantly, Jak2 regulates the accumulation of the cyclin D1 protein in the nucleus have recently reported that Jak2 controls the expression and h nuclear accumulation of cyclin D1. Because this particular D- through modification of the Akt1/GSK3 pathway, which type cyclin has been suggested to be a key mediator for ErbB2- mediates the phosphorylation and nuclear export of cyclin D1 associated mammary tumorigenesis, we deleted Jak2 from (6). The notion that cyclin D1 is a key target of the Jak/Stat pathway is supported by the fact that females deficient in cyclin ErbB2-expressing mammary epithelial cells prior to tumor onset and in neoplastic cells to address whether this tyrosine D1 exhibit impaired mammary gland development similar to Jak2 kinase plays a role in the initiation as well as progression of and Stat5 conditional knockout mice (7, 8). mammary cancer. Similar to cyclin D1–deficient mice, the The most pertinent functions of the PRL-R/Jak2/Stat5 signaling functional ablation of Jak2 protects against the onset of cascade and cyclin D1 are confined to alveolar progenitors that mammary tumorigenesis. In contrast, the deletion of Jak2 reside at the terminal ends of the ductal tree, a region known as from neoplastic cells or the acute, ligand-inducible down- lobular units in mice or terminal duct lobular units in humans regulation of this tyrosine kinase in an orthotopic transplant (9). This specific region in the breast seems to contain hormone- model did not affect the growth and survival of cancer cells. responsive epithelial cells that exhibit an elevated susceptibly to The constitutive activation of ErbB2 signaling, which is an neoplastic transformation depending on the reproductive status and the genetic predisposition. We previously demonstrated that initial event in the formation of mammary cancer, was able to override the functional role of Jak2 in regulating the in mice, alveolar progenitors facilitate mammary tumorigenesis in expression of Akt1 and cyclin D1. This might be a compen- multiparous females overexpressing ErbB2 (Her2/neu; ref. 10). A growth inhibition of this epithelial subtype through targeted satory mechanism that explains why Jak2 is a relevant target cyclin D1 for preventing the initiation but not the progression of ErbB2- deletion of the gene has been shown to significantly associated mammary cancer. [Cancer Res 2009;69(16):6642–50] reduce the onset of oncogenic Ras and ErbB2-induced mammary tumorigenesis (11, 12). Because signaling through Jak2 is important for the expression and nuclear accumulation of cyclin Introduction D1 in mammary epithelial cells, it was reasonable to propose that, like cyclin D1 deficiency, lack of Jak2 might significantly delay or In the developing mammary gland, the Janus kinase 2 (Jak2) is abolish the occurrence of ErbB2-associated mammary cancer in essential for the tyrosine phosphorylation and activation of the mice. To address this hypothesis, we generated two mouse models signal transducer and activator of transcription 5 (Stat5a and that overexpress the wild-type ErbB2 receptor in mammary Stat5b) in response to prolactin signaling (1, 2). Developmental epithelia that are conditionally deficient in Jak2. In addition to studies on genetically engineered mice which lack Jak2 and Stat5 examining whether signaling through Jak2 and Stat5 contributes conditionally at defined stages of mammogenesis showed that the to mammary cancer initiation, the targeted deletion of the Jak2 Jak2/Stat5 signaling pathway plays a pivotal role in the gene in fully neoplastic cells permitted us to determine whether proliferation and differentiation of alveolar cells during pregnancy inhibiting the activation of this pathway is also therapeutically (2, 3). Experimental evidence from different laboratories shows relevant to treat the established disease. The key findings of this that PRL signaling through the Jak2/Stat5 pathway is important study clearly show that the importance of Jak2 as a preventive or for the expression and functionality of cyclin D1 in proliferating therapeutic target for breast cancer varies greatly during tumor mammary epithelial cells. It has been suggested that PRL-R initiation and progression. signaling might indirectly modulate cyclin D1 expression through up-regulation of insulin-like growth factor-II (4). The expression of cyclin D1 is also directly regulated by PRL signaling through Materials andMethods Mouse models. Mouse mammary tumor virus (MMTV)-Cre and WAP- Cre transgenics (13) as well as Rosa-LacZ reporter mice (14) were crossed Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). with Jak2 conditional knockout mice. The generation of genetically fl/fl Requests for reprints: Kay-Uwe Wagner, Eppley Institute for Research in Cancer engineered animals with Jak2 conditional knockout alleles (Jak2 ) and and Allied Diseases, University of Nebraska Medical Center, 985950 Nebraska Medical the PCR protocols to determine the presence of the Jak2 floxed, Jak2 Center, Omaha, NE 68198-5950. Phone: 402-559-3288; Fax: 402-559-4651; E-mail: recombined/null, and Jak2 wild-type alleles have been described previously [email protected]. I2009 American Association for Cancer Research. (2, 15). Mice overexpressing the unactivated rat ErbB2 under regulation of doi:10.1158/0008-5472.CAN-09-0746 the MMTV long-terminal repeat (16) were obtained from The Jackson Cancer Res 2009; 69: (16). August 15, 2009 6642 www.aacrjournals.org Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 2009 American Association for Cancer Research. Published OnlineFirst July 28, 2009; DOI: 10.1158/0008-5472.CAN-09-0746 Jak2 in Mammary Cancer Initiation and Progression Figure 1. Complete inhibition of ErbB2/Neu-induced mammary tumorigenesis through deletion of Jak2. A, Kaplan-Meier survival curve. B, mammary gland whole-mounts from premenopausal and postmenopausal Jak2-deficient females and their controls. T, neoplastic lesion; LN, lymph node; bar, 0.5 cm. Laboratory. The targeted alleles and transgenes were carried in an FvB cells as well as a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium background (>50–97%), which facilitates Her2/neu-associated mammary bromide growth assay was performed according to a standard protocol tumorigenesis (10, 17). All animals used in this study were treated humanely (18). HC11 cells were cultured as described previously (19) and transfected and in accordance with institutional guidelines and federal regulations. with the pcDNA3 expression vector containing the activated mutant Cell cultures and expression vectors. Mammary cancer cells were form of the ErbB2/neu oncogene (kindly provided by Dr. W.J. Muller, fl/fl derived from tumor-bearing MMTV-neu Jak2 females and cultured in Royal Victoria Hospital, Montreal, Quebec, Canada). Cells were treated for DMEM/F12 medium as described previously (6). The generation of a 48 h with the Jak2 tyrosine kinase inhibitor tyrphostin (AG490; 50 Amol/L; retroviral vector expressing Cre recombinase was published by Krempler Calbiochem). and colleagues (18). Forty-eight hours after infection, cells were selected in Immunostaining. A basic protocol for immunohistochemistry on complete medium containing increasing concentrations (3–7 Ag/mL) of paraffin-embedded mammary gland specimens was described elsewhere puromycin (Sigma). Mammary cancer cells were treated with 10 nmol/L of (2). We used the following primary antibodies: a-cyclin D1 (Ab-4) from Lab PRL for 20 min to induce the phosphorylation of Stat5. A retroviral Vision, a-pAkt1 (Ser473; 736E11) and a-ErbB2 from Cell Signaling construct expressing the tetracycline-controlled transactivator (tTA) was Technology, a-phosphorylated Stat5A/B (Tyr694/699) from Upstate Biotech- cloned by inserting the tTA coding sequence into the blunted EcoRI site of nology, and a-Ki-67 (Tec-3) from Dako. For visualization of the specific the pBabe-puro vector. A myc-tagged cDNA of human Jak2 was cloned targets, we used corresponding biotinylated secondary antibodies and into the blunted BamHI site of the retroviral pRevTRE vector (Clontech Vectastain Elite ABC kits (Vector Laboratories). Laboratories, Inc.). After generating hygromycin (100 Ag/mL) and Immunoprecipitation and Western blot analysis. The preparation of puromycin double-resistant clones that express exogenous Jak2 in a whole-cell extracts of clarified cell lysates and tissue homogenates as well as doxycycline-controlled manner, we used the AdCreGFP vector
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