Janus kinase 2 (commonly called JAK2) is a non-receptor tyrosine kinase. It is a member of the Janus kinase family and has been implicated in signaling by members of the type II cytokine receptor family (e.g. interferon receptors). Here we’d like to share a latest research about JAK2 gene in breast cancer. This article comes from www.sciencemag.org and www.ScienceTranslationalMedicine.org and you can get all detail from these sites. what’s more, Creative Biomart can provide you product related to JAK2 of several sources, grades and formulations for research applications.
INTRODUCTION
Triple-negative breast cancer (TNBC) is the more lethal subtype of this disease, most of which exhibit basal-like patterns of gene expression. Currently, TNBC lacks clinically approved molecularly targeted therapies and is primarily treated with traditional chemotherapy and surgery. Although neoadjuvant (presurgery) chemotherapy (NAC) can be effective in eradicating TNBCs in the breast in about 30% of patients, many tumors do not respond or respond partially, eventually recurring as distant metastases. We and others have identified potential molecular mechanisms of drug resistance and poor outcome in TNBC. Some of these alterations are potentially actionable or targetable with molecularly directed therapies in clinical development.
The mammalian JAK-STAT signaling pathway comprises four JAK domain–containing proteins [JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2)] and seven STAT proteins (STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6). Deregulation of this pathway has been implicated in the promotion of oncogenic phenotypes, including tumorigenesis, invasion, metastasis, proliferation, survival, angiogenesis, antiapoptosis, and immune evasion. In breast cancer, the JAK-STAT pathway has been shown to be altered by the following mechanisms: (i) down-regulation of phosphotyrosinespecific phosphatases; (ii) increase in the amount of the JAK/ STAT-activating ligand interleukin-6 (IL-6); (iii) activation of other upstream oncogenic pathways, such as ErbB1, c-Src, or phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR); and (iv) down-regulation of negative regulators of STAT such as suppressor of cytokine signaling 3 (SOCS3).
Here, we demonstrate that a fraction of TNBCs harbor amplifications at the 9p24.1 locus, which includes JAK2. The copy number of the 9p24 amplicon increased during selection by chemotherapy and the development of metastasis, suggesting a role in tumor progression and therapeutic resistance. We found that JAK2 drives a JAK1/STAT3-independent signaling program that can be overcome using JAK2-specific inhibitors in combination with chemotherapy to reduce tumor-initiating stem cell–like cells and to suppress tumor growth and progression.
Study design
This study was designed to evaluate the role of JAK2 amplifications observed through NGS efforts in TNBCs. Demonstration of JAK2 amplifications in clinical samples was used to justify cell culture and in vivo (xenograft and PDX) models demonstrating that JAK2 may be a useful target in TNBCs, particularly those with amplifications of the JAK2 locus (9p24). For mouse studies, randomization to individual treatment groups was made once tumors reached a target of 100 to 500 mm3, depending on the tumor model. All experiments were replicated at least twice for a total of three independent experiments. Studies or experiments with more than three replicates are noted in the figure legends.
RESULTS
JAK2 signaling affects mammosphere potential. Because JAK/STAT signaling plays a role in stem cell functionality and self-renewal, we determined whether specific siRNA knockdown of JAK1 (siJAK1), JAK2 (siJAK2), or both JAK1 and JAK2 (siJAK1/2) or treatment with ruxolitinib would affect mammosphere formation, a marker of the tumor-initiating or cancer stem cell-like population. We found that in both HCC-38 (JAK2GAIN) and MDA-436 (JAK2AMP), siJAK1 enhanced mammosphere formation, but siJAK2 reduced mammosphere-forming ability. The effect of JAK1 knockdown with siRNA in HCC-38 cells was abrogated by JAK2 knockdown when both siRNAs (siJAK1/2) were used in combination. Consistent with this result, ruxolitinib (JAK1/2 inhibitor)–treated HCC-38 cells also exhibited increased mammosphere formation compared to untreated cells, although the same result was not observed in MDA-436 cells. In these cells, siJAK2 and siJAK1/2, but not siJAK1, inhibited mammospheres to the same degree, suggesting a dominant JAK2-specific effect. Once again, the effect of JAK1/2 knockdown on mammosphere formation in MDA-436 cells was phenocopied by JAK1/2 inhibition with ruxolitinib.
We next used JAK2-targeted short hairpin RNAs (shRNA) in a doxycycline-inducible vector. To select for cells with mammosphere forming capacity, cells were treated with paclitaxel, a chemotherapeutic drug known to spare cancer stem cell–like with tumor-initiating capacity. In both HCC-38 and MDA-436 cells, doxycycline-induced inhibition of JAK2 abrogated the enrichment of mammosphere-forming, drug-resistant cells spared by paclitaxel. Inducible JAK2 knockdown was confirmed by immunoblot. Pharmacological inhibition with the JAK2-specific inhibitor BSK805 produced similar results in both cell lines, further suggesting that the inhibition of mammospheres is a JAK2-specific effect. A continued effect of JAK2 inhibition or inducible shJAK2 on mammosphere potential was observed when HCC-38 mammospheres were dissociated and replated in a secondary sphere formation assay. To directly assess tumorigenic potential, we performed a limiting dilution of MDA-436 or HCC-38 cells (1 × 106, 1 × 105, or 1 × 104 cells) injected orthotopically into nude mice, with or without pretreatment with BSK805 or vehicle control, or using doxycycline-inducible shRNAs [nontargeting shRNA control (shNTC) or shJAK2] pretreated with doxycycline. shJAK2 induction significantly reduced the tumorigenic population of both cell lines (P = 2.49 × 10−7 and P = 6.23 × 10−8 in MDA-436 and HCC-38 cells, respectively), whereas BSK805 was effective in reducing thetumor-initiating populationin MDA-436 cells but not in HCC-38 cells. However, the HCC-38 model often forms small dormant nodules that inconsistently develop into malignant tumors, complicating the analysis of the results with this cell line.
Although JAK2-specific inhibition did not have substantial antitumor effects in any of the four models, JAK2 inhibition overcame intrinsic docetaxel resistance in the PDXs with JAK2GAIN. Collectively, these results suggest that therapeutic benefit may be obtained from the addition of JAK2-specific inhibitors to chemotherapy in breast cancers with JAK2 copy gains or gene amplification.
The article origin: www.ScienceTranslationalMedicine.org 13 April 2016 Vol 8 Issue 334 334ra53.
[table caption=”Related Products” width=”800″ colwidth=”80|180|180″ colalign=”left|left|center|center|center”]
Cat. #,Product name,Source(Host),Species,Conjugate
JAK2-3136R,Recombinant Rat JAK2 Protein,Mammalian Cells,Rat,His
JAK2-26H,Recombinant Human JAK2 protein MYC/DDK-tagged,HEK293,Human,MYC/DDK
JAK2-2327R,Recombinant Rhesus monkey JAK2 Protein His-tagged,Mammalian Cells,Rhesus monkey,His
JAK2-250H,Recombinant Human JAK2,Mammalian Cells,Human,His
JAK2-336H,Recombinant Human JAK2 protein GST-tagged,Insect cells,Human,GST
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