title: Barcoding reveals complex clonal dynamics of de novo transformed human mammary cells.
abstract: Most human breast cancers have diversified genomically and biologically by the time they become clinically evident. Early events involved in their genesis and the cellular context in which these events occur have thus been difficult to characterize. Here we present the first formal evidence of the shared and independent ability of basal cells and luminal progenitors, isolated from normal human mammary tissue and transduced with a single oncogene (KRAS(G12D)), to produce serially transplantable, polyclonal, invasive ductal carcinomas within 8 weeks of being introduced either subrenally or subcutaneously into immunodeficient mice. DNA barcoding of the initial cells revealed a dramatic change in the numbers and sizes of clones generated from them within 2 weeks, and the first appearance of many 'new' clones in tumours passaged into secondary recipients. Both primary and secondary tumours were phenotypically heterogeneous and primary tumours were categorized transcriptionally as 'normal-like'. This system challenges previous concepts that carcinogenesis in normal human epithelia is necessarily a slow process requiring the acquisition of multiple driver mutations. It also presents the first description of initial events that accompany the genesis and evolution of malignant human mammary cell populations, thereby contributing new understanding of the rapidity with which heterogeneity in their properties can develop.
authors.affiliation: Terry Fox Laboratory, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: Long V
authors.initials: LV
authors.lastname: Nguyen
authors.affiliation: Terry Fox Laboratory, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada.|Department of Medical Genetics, University of British Columbia, Vancouver, British ColumbiaV6T 2B5, Canada.
authors.forename: Davide
authors.initials: D
authors.lastname: Pellacani
authors.affiliation: Terry Fox Laboratory, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Lefort
authors.affiliation: Terry Fox Laboratory, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada.|Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada.
authors.forename: Nagarajan
authors.initials: N
authors.lastname: Kannan
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada.|Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: Tomo
authors.initials: T
authors.lastname: Osako
authors.affiliation: Terry Fox Laboratory, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: Maisam
authors.initials: M
authors.lastname: Makarem
authors.affiliation: Terry Fox Laboratory, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: Claire L
authors.initials: CL
authors.lastname: Cox
authors.affiliation: Terry Fox Laboratory, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: William
authors.initials: W
authors.lastname: Kennedy
authors.affiliation: Terry Fox Laboratory, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: Philip
authors.initials: P
authors.lastname: Beer
authors.affiliation: Centre for High-Throughput Biology, Department of Microbiology &Immunology, University of British Columbia, 2125 East Mall, Vancouver, British Columbia V6T 1Z4, Canada.
authors.forename: Annaick
authors.initials: A
authors.lastname: Carles
authors.affiliation: Centre for High-Throughput Biology, Department of Microbiology &Immunology, University of British Columbia, 2125 East Mall, Vancouver, British Columbia V6T 1Z4, Canada.
authors.forename: Michelle
authors.initials: M
authors.lastname: Moksa
authors.affiliation: Centre for High-Throughput Biology, Department of Microbiology &Immunology, University of British Columbia, 2125 East Mall, Vancouver, British Columbia V6T 1Z4, Canada.|Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: Misha
authors.initials: M
authors.lastname: Bilenky
authors.affiliation: Terry Fox Laboratory, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: Sneha
authors.initials: S
authors.lastname: Balani
authors.affiliation: Terry Fox Laboratory, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: Sonja
authors.initials: S
authors.lastname: Babovic
authors.affiliation: Biomedical Physiology and Kinesiology, Simon Fraser University, 8888 University Drive, Burnaby, British Columbia V5A 1S6, Canada.|Cancer Control Unit, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: Ivan
authors.initials: I
authors.lastname: Sun
authors.affiliation: Biomedical Physiology and Kinesiology, Simon Fraser University, 8888 University Drive, Burnaby, British Columbia V5A 1S6, Canada.|Cancer Control Unit, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: Miriam
authors.initials: M
authors.lastname: Rosin
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada.|Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: Samuel
authors.initials: S
authors.lastname: Aparicio
authors.affiliation: Centre for High-Throughput Biology, Department of Microbiology &Immunology, University of British Columbia, 2125 East Mall, Vancouver, British Columbia V6T 1Z4, Canada.|Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Hirst
authors.affiliation: Terry Fox Laboratory, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada.|Department of Medical Genetics, University of British Columbia, Vancouver, British ColumbiaV6T 2B5, Canada.
authors.forename: Connie J
authors.initials: CJ
authors.lastname: Eaves
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000503:physiopathology*; D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000503:physiopathology*; D019070:Cell Lineage / Q000235:genetics; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D058893:DNA Barcoding, Taxonomic; D005260:Female; D020869:Gene Expression Profiling; D064593:Heterografts; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D042361:Mammary Glands, Human / Q000166:cytology / Q000503:physiopathology*; D051379:Mice; D008815:Mice, Inbred Strains; D016513:Mice, SCID; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D013997:Time Factors; D014161:Transduction, Genetic; D018631:ras Proteins / Q000235:genetics
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins