title: Retinoic acid directs breast cancer cell state changes through regulation of TET2-PKCζ pathway.
abstract: The key molecular mechanism governing the cancer cell state (stem cell-like state vs differentiation state) to control the cancer stem cell (CSC) pool remains elusive. This study provides the first evidence showing that all-trans retinoic acid (ATRA) induces the interaction and chromatin recruitment of a novel RARβ-TET2 complex to epigenetically activate a specific cohort of gene targets, including MiR-200c. TET2-activated miR-200c further targets and suppresses PKCζ, a cell polarity protein that has a pivotal role in directing asymmetric division of mammalian stem cells to sustain the stem cell pool. Our data reveal that pharmacological concentration of ATRA effectively downregulates PKCζ through activation of miR-200c, leading to a decrease of the stem cell-like populations from non-tumorigenic mammary epithelial cells and non-aggressive breast cancer cells. However, aggressive breast cancer cells that manifest TET2-miR-200c dysregulation sustain a CSC pool highly resistant to ATRA, where inhibition of PKCζ directs the resistant CSCs to the luminal cell-like state and sensitization to tamoxifen, resulting in abrogation of mammary tumor growth and progression. Together, these findings elucidate a novel RARβ-TET2-miR-200c-PKCζ signaling pathway that directs cancer cell state changes and also provide previously unidentified therapeutic implications for PKCζ inhibitors in diminishment of breast CSCs to eradicate breast cancer.
authors.affiliation: Department of Basic Medical Sciences, Purdue University, West Lafayette, IN, USA.|Center for Cancer Research, Purdue University, West Lafayette, IN, USA.
authors.forename: M-J
authors.initials: MJ
authors.lastname: Wu
authors.affiliation: Department of Basic Medical Sciences, Purdue University, West Lafayette, IN, USA.|Center for Cancer Research, Purdue University, West Lafayette, IN, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: Kim
authors.affiliation: Department of Basic Medical Sciences, Purdue University, West Lafayette, IN, USA.|Center for Cancer Research, Purdue University, West Lafayette, IN, USA.
authors.forename: Y-S
authors.initials: YS
authors.lastname: Chen
authors.affiliation: Department of Basic Medical Sciences, Purdue University, West Lafayette, IN, USA.|Center for Cancer Research, Purdue University, West Lafayette, IN, USA.
authors.forename: J-Y
authors.initials: JY
authors.lastname: Yang
authors.affiliation: Department of Basic Medical Sciences, Purdue University, West Lafayette, IN, USA.|Center for Cancer Research, Purdue University, West Lafayette, IN, USA.
authors.forename: C-J
authors.initials: CJ
authors.lastname: Chang
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism*; D049308:Dioxygenases; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D011493:Protein Kinase C / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D014212:Tretinoin; D049308:Dioxygenases; C551914:Tet2 protein, mouse; D011493:Protein Kinase C