title: Tumor initiating but differentiated luminal-like breast cancer cells are highly invasive in the absence of basal-like activity.
abstract: The majority of human breast cancers exhibit luminal epithelial differentiation. However, most aggressive behavior, including invasion and purported cancer stem cell activity, are considered characteristics of basal-like cells. We asked the following questions: Must luminal-like breast cancer cells become basal-like to initiate tumors or to invade? Could luminally differentiated cells within a basally initiated hierarchy also be tumorigenic? To answer these questions, we used rare and mutually exclusive lineage markers to isolate subsets of luminal-like and basal-like cells from human breast tumors. We enriched for populations with or without prominent basal-like traits from individual tumors or single cell cloning from cell lines and recovered cells with a luminal-like phenotype. Tumor cells with basal-like traits mimicked phenotypic and functional behavior associated with stem cells assessed by gene expression, mammosphere formation and lineage markers. Luminal-like cells without basal-like traits, surprisingly, were fully capable of initiating invasive tumors in NOD SCID gamma (NSG) mice. In fact, these phenotypically pure luminal-like cells generated larger and more invasive tumors than their basal-like counterparts. The tumorigenicity and invasive potential of the luminal-like cancer cells relied strongly on the expression of the gene GCNT1, which encodes a key glycosyltransferase controlling O-glycan branching. These findings demonstrate that basal-like cells, as defined currently, are not a requirement for breast tumor aggressiveness, and that within a single tumor there are multiple "stem-like" cells with tumorigenic potential casting some doubt on the hypothesis of hierarchical or differentiative loss of tumorigenicity.
authors.affiliation: Department of Cellular and Molecular Medicine, Centre for Biological Disease Analysis and Danish Stem Cell Centre, Faculty of Health Sciences,  University of Copenhagen, DK-2200 Copenhagen N,  Denmark.
authors.forename: Jiyoung
authors.initials: J
authors.lastname: Kim
authors.forename: René
authors.initials: R
authors.lastname: Villadsen
authors.forename: Therese
authors.initials: T
authors.lastname: Sørlie
authors.forename: Louise
authors.initials: L
authors.lastname: Fogh
authors.forename: Signe Z
authors.initials: SZ
authors.lastname: Grønlund
authors.forename: Agla J
authors.initials: AJ
authors.lastname: Fridriksdottir
authors.forename: Irene
authors.initials: I
authors.lastname: Kuhn
authors.forename: Fritz
authors.initials: F
authors.lastname: Rank
authors.forename: Vera Timmermans
authors.initials: VT
authors.lastname: Wielenga
authors.forename: Hiroko
authors.initials: H
authors.lastname: Solvang
authors.forename: Paul A W
authors.initials: PA
authors.lastname: Edwards
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Børresen-Dale
authors.forename: Lone
authors.initials: L
authors.lastname: Rønnov-Jessen
authors.forename: Mina J
authors.initials: MJ
authors.lastname: Bissell
authors.forename: Ole William
authors.initials: OW
authors.lastname: Petersen
mesh_terms: D000068816:Adapalene; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency / Q000235:genetics; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D008819:Mice, Nude; D018396:Mucin-1 / Q000378:metabolism; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics / Q000378:metabolism; D009281:Naphthalenes / Q000378:metabolism; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: C507942:Il2rg protein, mouse; D053631:Interleukin Receptor Common gamma Subunit; D018396:Mucin-1; D009281:Naphthalenes; D000068816:Adapalene; D017351:N-Acetylglucosaminyltransferases; C053024:beta-1,3-galactosyl-O-glycosyl-glycoprotein beta-1,6-acetylglucosaminyl transferase