ABSTRACT
Dr Egeland is senior director of business development and licensing in the Early Technologies business unit of the Minimally Invasive Therapies Group at Medtronic. Mr Rapp is an associate consultant at Pharmagellan, a biotech consultancy. Dr David is the founder and managing director of Pharmagellan.
Subject(s)
Financial Management, Hospital , Health Care Sector/economics , Inventions/economics , Surgical Instruments/economics , Humans , SurgeonsABSTRACT
Chromatin-mediated processes influence the development and progression of breast cancer. Using murine mammary carcinoma-derived tumorspheres as a functional readout for an aggressive breast cancer phenotype, we performed a loss-of-function screen targeting 60 epigenetic regulators. We identified the Polycomb protein Cbx8 as a key regulator of mammary carcinoma both in vitro and in vivo. Accordingly, Cbx8 is overexpressed in human breast cancer and correlates with poor survival. Our genomic analyses revealed that Cbx8 positively regulates Notch signaling by maintaining H3K4me3 levels on Notch-network gene promoters. Ectopic expression of Notch1 partially rescues tumorsphere formation in Cbx8-depleted cells. We find that Cbx8 associates with non-PRC1 complexes containing the H3K4 methyltransferase complex component WDR5, which together regulate Notch gene expression. Thus, our study implicates a key non-canonical role for Cbx8 in promoting breast tumorigenesis.
Subject(s)
Mammary Neoplasms, Animal/metabolism , Mitochondrial Membrane Transport Proteins/physiology , Polycomb-Group Proteins/physiology , Proteins/physiology , Animals , Carcinogenesis/metabolism , Cell Line, Tumor , Epigenesis, Genetic , Epithelial Cells/metabolism , Female , Gene Expression , Gene Expression Regulation, Neoplastic , Genetic Loci , Histones/metabolism , Humans , Intracellular Signaling Peptides and Proteins , Mammary Neoplasms, Animal/genetics , Mammary Neoplasms, Animal/pathology , Mice, Transgenic , Neoplastic Stem Cells/metabolism , Polycomb Repressive Complex 1 , Protein Processing, Post-Translational , Receptors, Notch/genetics , Receptors, Notch/metabolism , Signal Transduction , Spheroids, Cellular/metabolism , Tumor BurdenABSTRACT
Phosphatase and tensin homolog on chromosome ten (PTEN) is a tumor suppressor and an antagonist of the phosphoinositide-3 kinase (PI3K) pathway. We identified a 576-amino acid translational variant of PTEN, termed PTEN-Long, that arises from an alternative translation start site 519 base pairs upstream of the ATG initiation sequence, adding 173 N-terminal amino acids to the normal PTEN open reading frame. PTEN-Long is a membrane-permeable lipid phosphatase that is secreted from cells and can enter other cells. As an exogenous agent, PTEN-Long antagonized PI3K signaling and induced tumor cell death in vitro and in vivo. By providing a means to restore a functional tumor-suppressor protein to tumor cells, PTEN-Long may have therapeutic uses.
