Oncogenic features of neuromedin U in breast cancer are associated with NMUR2 expression involving crosstalk with members of the WNT signaling pathway
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Stefan Garczyk1, Natalie Klotz1, Sabrina Szczepanski1, Bernd Denecke2, Wiebke Antonopoulos1, Saskia von Stillfried1, Ruth Knüchel1, Michael Rose1,* and Edgar Dahl1,*
1Molecular Oncology Group, Institute of Pathology, Medical Faculty of the RWTH Aachen University, D-52074 Aachen, Germany
2IZKF Aachen, Medical Faculty of the RWTH Aachen University, D-52074 Aachen, Germany
*Equal co-senior authors
Stefan Garczyk, email: [email protected]
Keywords: breast cancer, metastasis, neuromedin U, neuromedin U receptor 2, WNT signaling
Received: December 20, 2016 Accepted: February 07, 2017 Published: March 11, 2017
Neuromedin U (NMU) has been shown driving the progression of various tumor entities, including breast cancer. However, the expression pattern of NMU and its receptors in breast cancer tissues as well as systematic insight into mechanisms and downstream targets of the NMU-driven signaling pathways are still elusive. Here, NMU expression was found up-regulated in all breast cancer subtypes when compared to healthy breast tissue. Using an in silico dataset comprising 1,195 samples, high NMU expression was identified as an indicator of poor outcome in breast tumors showing strong NMUR2 expression. Next, the biological impact of NMU on breast cancer cells in relation to NMUR2 expression was analyzed. Ectopic NMU expression reduced colony growth while promoting a motile phenotype in NMUR2-positive SKBR3 but not NMUR2-negative Hs578T cells. To uncover signaling pathways and key molecules affected by NMU in SKBR3 cells, Affymetrix microarray analysis was applied. Forced NMU expression affected molecules involved in WNT receptor signaling among others. As such we demonstrated enhanced activation of the WNT/planar cell polarity (PCP) effector RAC1 and down-regulation of canonical WNT targets such as MYC. In summary, NMU might contribute to progression of NMUR2-positive breast cancer representing a potential druggable target for future personalized strategies.
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