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Marsha Rosner, PhDProfessor of The Ben May Department for Cancer ResearchThe Rosner laboratory focuses on the mechanism by which signals are transmitted within the cell to specify particularoutputs leading to cell growth, differentiation or death. Dr. Rosner’s long-time focus has been on the regulation of the MAPkinase signaling cascade, an evolutionarily conserved kinase pathway that has been implicated in tumor cell progression,invasion and metastasis. Recent work from the laboratory has elucidated novel signaling cascades that regulate tumorcell cycle progression and metastasis via mechanisms involving microRNAs. One aspect of Dr. Rosner’s work involvescharacterizing the mechanism by which Raf Kinase Inhibitory Protein (RKIP), functions as a suppressor of breast cancermetastasis.Cell Signaling &Gene RegulationTumor metastasis suppressors are inhibitors of metastatic progression and colonization and, as such, represent importantmarkers for prognosis and potential effectors of therapeutic treatment. However, the mechanisms by which metastasissuppressors function are generally not understood. RKIP has been implicated as a suppressor of lung metastasis in a murinemodel using androgen-independent prostate tumor cells. A modulator of key regulatory pathways in mammalian cells, RKIPinhibits MAP kinase (MAPK) signaling by binding to Raf-1, preventing Raf-1 phosphorylation at activating sites. RKIP alsosuppresses NFkB activation, inhibits GRK2-mediated downregulation of G protein-coupled receptors, and potentiates theefficacy of chemotherapeutic agents. The Rosner laboratory has recently shown that RKIP ensures chromosomal integrityand genomic stability by preventing MAPK inhibition of Aurora B kinase and the spindle checkpoint. RKIP is missing ordepleted in a number of cancers including prostate, breast, melanoma, hepatocellular, and colorectal, suggesting that it mayfunction as a general metastasis suppressor for solid tumors. The Rosner laboratory has analyzed gene expression data fromprimary human breast tumors and determined that the RKIP signaling pathway is a prognostic marker for metastasis-freesurvival of breast cancer patients.Dr. Rosner’s recent studies have shown that RKIP suppresses invasion and metastasis by inhibiting the MAP kinase (MAPK)signaling pathway and inducing the microRNA let-7. MicroRNAs are noncoding RNAs of ~22 nucleotides that regulate keyprocesses in growth and development and have been implicated as tumor oncogenes or suppressors in cancer. Let-7/miR-98is an evolutionarily conserved microRNA family that has been implicated as a tumor suppressor of colon and lung cancer, andlet-7 loss is associated with breast tumors as well as other less differentiated human cancer cells. Let-7 has also been shownto suppress breast cancer stem cell properties (self-replication and pluripotent differentiation to multiple cell types) as well asproliferation and breast tumor growth. Thus the microRNA let-7 is an important link between regulation of metastasis andregulation of embryonic and cancer stem cells.Although let-7 has been implicated as a suppressor of breast cancer metastasis, few of its downstream signaling targets areknown. To determine which potential let-7 targets regulate metastatic progression upon loss of RKIP expression, The Rosnerlaboratory, in collaboration with Dr. Andy Minn, developed a new strategy based on gene set analysis of gene expressiondata from >1200 human breast tumors. The goal was to negatively correlate expression of putative let-7 targets with RKIPexpression. A similar approach was used to identify bone metastasis signature (BMS) genes that might be regulated by RKIP.The Rosner laboratory identified a novel RKIP/let-7-regulated signaling cascade, involving transcription factors that regulatekey BMS genes, and enabled the use of this cascade in predicting metastatic risk in patients. Dr. Rosner hopes to test thesepredictions in the clinic to determine their prognostic and therapeutic potential for both identifying patients most likely tosuffer metastatic disease as well as to identify the most effective treatments.UCCRC SCIENTIFIC REPORT 200911