title: Delineation of breast cancer cell hierarchy identifies the subset responsible for dormancy.
abstract: The bone marrow (BM) is a major organ of breast cancer (BC) dormancy and a common source of BC resurgence. Gap junctional intercellular communication (GJIC) between BC cells (BCCs) and BM stroma facilitates dormancy. This study reports on a hierarchy of BCCs with the most immature subset (Oct4(hi)/CD44(hi/med)/CD24(-/+)) demonstrating chemoresistance, dormancy, and stem cell properties: self-renewal, serial passaging ability, cycling quiescence, long doubling time, asymmetric division, high metastatic and invasive capability. In vitro and in vivo studies indicated that this subset was responsible for GJIC with BM stroma. Similar BCCs were detected in the blood of patients despite aggressive treatment and in a patient with a relatively large tumor but no lymph node involvement. In brief, these findings identified a novel BCC subset with stem cell properties, with preference for dormancy and in the circulation of patients. The findings establish a working cellular hierarchy of BCCs based on phenotype and functions.
authors.affiliation: Department of Medicine - Division of Hematology/Oncology, New Jersey Medical School, University of Medicine and Dentistry of New Jersey , Newark, NJ, USA.
authors.forename: Shyam A
authors.initials: SA
authors.lastname: Patel
authors.forename: Shakti H
authors.initials: SH
authors.lastname: Ramkissoon
authors.forename: Margarette
authors.initials: M
authors.lastname: Bryan
authors.forename: Lillian F
authors.initials: LF
authors.lastname: Pliner
authors.forename: Gabriela
authors.initials: G
authors.lastname: Dontu
authors.forename: Prem S
authors.initials: PS
authors.lastname: Patel
authors.forename: Sohrab
authors.initials: S
authors.lastname: Amiri
authors.forename: Sharon R
authors.initials: SR
authors.lastname: Pine
authors.forename: Pranela
authors.initials: P
authors.lastname: Rameshwar
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051927:CD24 Antigen / Q000235:genetics / Q000378:metabolism; D016190:Carboplatin / Q000494:pharmacology / Q000627:therapeutic use; D002450:Cell Communication / Q000187:drug effects / Q000235:genetics*; D002455:Cell Division; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D005260:Female; D017629:Gap Junctions / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D015398:Signal Transduction; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D051927:CD24 Antigen; C497889:CD24 protein, human; C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D016190:Carboplatin