Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.1.99.3 (PRE)
 1,923 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fibroblast growth factor (FGF) receptor 2 (FGFR-2) polymorphisms have been associated with an increase in estrogen receptor and progesterone receptor (PR)-positive breast cancer risk; however, a clear mechanistic association between FGFR-2 and steroid hormone receptors remains elusive. In previous works, we have shown a cross talk between FGF2 and progestins in mouse mammary carcinomas. To investigate the mechanisms underlying these interactions and to validate our findings in a human setting, we have used T47D human breast cancer cells and human cancer tissue samples. We showed that medroxyprogesterone acetate (MPA) and FGF2 induced cell proliferation and activation of ERK, AKT, and STAT5 in T47D and in murine C4-HI cells. Nuclear interaction between PR, FGFR-2, and STAT5 after MPA and FGF2 treatment was also showed by confocal microscopy and immunoprecipitation. This effect was associated with increased transcription of PRE and/or GAS reporter genes, and of PR/STAT5-regulated genes and proteins. Two antiprogestins and the FGFR inhibitor PD173074, specifically blocked the effects induced by FGF2 or MPA respectively. The presence of PR/FGFR-2/STAT5 complexes bound to the PRE probe was corroborated by using NoShift transcription and chromatin immunoprecipitation of the MYC promoter. Additionally, we showed that T47D cells stably transfected with constitutively active FGFR-2 gave rise to invasive carcinomas when transplanted into NOD/SCID mice. Nuclear colocalization between PR and FGFR-2/STAT5 was also observed in human breast cancer tissues. This study represents the first demonstration of a nuclear interaction between FGFR-2 and STAT5, as PR coactivators at the DNA progesterone responsive elements, suggesting that FGFRs are valid therapeutic targets for human breast cancer treatment.
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PMID:Interaction between FGFR-2, STAT5, and progesterone receptors in breast cancer. 2146 42

Medulloblastoma (MB) is the most prevalent malignant brain tumor in children, accounting for 20% of all childhood brain tumors. The molecular profiling of MB into 4 major subgroups (WNT, SHH, Grp3, and Grp4) emphasizes the heterogeneity of MB and opens paths in which treatments may be targeted to molecularly aggressive and distinct tumors. Current therapeutic strategies for Group 3 MB are challenging and can be accompanied by long-term side effects from treatment. The involvement of altered epigenetic machinery in neoplastic transformation in MB has become more evident. Thus, we performed an epigenomic RNAi and chemical screen and identified SETD8/PRE-SET7/KMT5a as a critical player in maintaining proliferation and cell survival of MB cells. We have found that inhibition of SETD8 effects the migration/invasive ability of MB cells. SETD8 alters H4K20me chromatin occupancy at key genes involved in tumor invasiveness and pluripotency. Interestingly, these results link the aggressive and metastatic behavior of MYC-driven MB with SETD8 activity. Based on our results, we suggest that SETD8 has a critical role mediating Group 3 MB tumorigenesis. Establishing a role for SETD8 as a factor in MYC-driven MB has potential to lead to more effective therapies needed to improve outcomes in high-risk patients.
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PMID:Combined functional genomic and chemical screens identify SETD8 as a therapeutic target in MYC-driven medulloblastoma. 3062 40