• A Role For RUNX2 And TAZ In Promoting A Tumorigenic Phenotype In Luminal Breast Cancer Cells

      Brusgard, Jessica; Passaniti, Antonino (2014)
      Breast cancer (BC) is the second leading cause of cancer-associated deaths among women. Current strategies aimed at eradicating the primary tumor by targeting the bulk population of cells often leads to BC recurrence and metastasis because of intratumoral heterogeneity and treatment resistance. The RUNX2 transcription factor is upregulated in early stage luminal BC and is a poor prognostic indicator of patient survival. However, the precise mechanisms by which RUNX2 regulates an oncogenic phenotype in early stage tumors are not known. We now show for the first time that RUNX2 promotes luminal BC cell tumorsphere formation, which was inhibited with a novel RUNX2-targeting drug. RUNX2 associated with the TAZ transcriptional coactivator in MCF7 cells to promote a tumorigenic phenotype that was inhibited by siRNA-targeted knockdown of TAZ. TGFβ treatment of cells expressing RUNX2 increased endogenous TAZ translocation to the nucleus, a process that was prevented by inhibiting RUNX2. This translocation was preceded by disruption of adherens junctions through ectodomain shedding of an oncogenic soluble E-Cadherin fragment (80kDa sE-Cad). RUNX2 expression increased HER2-mediated tumorsphere formation, which was abrogated after treatment with the HER2-targeting agents Herceptin and Lapatinib. These data support a novel role for RUNX2 in promoting early stage tumorigenesis in the context of TGFβ, the Hippo signaling mediator TAZ, sE-Cad, and HER2. Using this signaling pathway to monitor BC cell oncogenic activity will allow us to discover new anti-cancer agents. Further characterization of RUNX2-targeted compounds that disrupt this oncogenic pathway could have therapeutic potential.