title: RUNX2 and TAZ-dependent signaling pathways regulate soluble E-Cadherin levels and tumorsphere formation in breast cancer cells.
abstract: Intratumoral heterogeneity and treatment resistance drive breast cancer (BC) metastasis and recurrence. The RUNX2 transcription factor is upregulated in early stage luminal BC. However, the precise mechanism by which RUNX2 regulates an oncogenic phenotype in luminal BCs remains an enigma. We show that RUNX2 is predictive of poor overall survival in BC patients. RUNX2 associated with the TAZ transcriptional co-activator to promote a tumorigenic phenotype that was inhibited by knockdown of TAZ. RUNX2 increased endogenous TAZ translocation to the nucleus, which was prevented by inhibiting RUNX2. RUNX2/TAZ interaction was associated with ectodomain shedding of an oncogenic soluble E-Cadherin fragment (sE-Cad), which is known to cooperate with human epidermal growth factor receptor-2 (HER2/ErbB2) to increase BC growth. Neutralizing E-Cadherin antibodies or TAZ knockdown reduced the levels of sE-Cad in RUNX2-expressing BC cells and inhibited tumorsphere formation. RUNX2 expression also increased HER2-mediated tumorsphere size, which was reduced after treatment with the HER2-targeting agents Herceptin and lapatinib. These data support a novel role for RUNX2 in promoting an oncogenic phenotype in luminal BC in the context of TAZ, sE-Cad, and HER2. Using this signaling pathway to monitor BC cell oncogenic activity will accelerate the discovery of new therapeutic modalities to treat BC patients.
authors: Program in Molecular Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.|Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.
authors: Jessica L
authors: JL
authors: Brusgard
authors: Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.|Laboratory of Genitourinary Cancer Pathogenesis, NCI, Bethesda, MD, USA.
authors: Moran
authors: M
authors: Choe
authors: Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.|Department of Hematology/Oncology, Mayo Clinic, Jacksonville, FL, USA.
authors: Saranya
authors: S
authors: Chumsri
authors: Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.
authors: Keli
authors: K
authors: Renoud
authors: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, USA.
authors: Alexander D
authors: AD
authors: MacKerell
authors: Mechanobiology Institute, Department of Physiology, National University of Singapore, Singapore.
authors: Marius
authors: M
authors: Sudol
authors: Department of Pathology and Department of Biochemistry & Molecular Biology, The Marlene & Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.|The Veteran's Health Administration Research & Development Service, Baltimore, MD, USA.
authors: Antonino
authors: A
authors: Passaniti
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015820:Cadherins / Q000378:metabolism*; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism*; D004318:Doxycycline / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D061986:MCF-7 Cells; D051379:Mice; D041681:NIH 3T3 Cells; D011485:Protein Binding; D034622:RNA Interference; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D012995:Solubility; D018874:Spheroids, Cellular / Q000187:drug effects / Q000378:metabolism*; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins
chemical_list: D015820:Cadherins; D050659:Core Binding Factor Alpha 1 Subunit; D004318:Doxycycline; D047908:Intracellular Signaling Peptides and Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; C551991:WWTR1 protein, human
keywords: breast cancer; therapeutics; transcription factors; tumorspheres