title: Somatic Cell Fusions Reveal Extensive Heterogeneity in Basal-like Breast Cancer.
abstract: Basal-like and luminal breast tumors have distinct clinical behavior and molecular profiles, yet the underlying mechanisms are poorly defined. To interrogate processes that determine these distinct phenotypes and their inheritance pattern, we generated somatic cell fusions and performed integrated genetic and epigenetic (DNA methylation and chromatin) profiling. We found that the basal-like trait is generally dominant and is largely defined by epigenetic repression of luminal transcription factors. Definition of super-enhancers highlighted a core program common in luminal cells but a high degree of heterogeneity in basal-like breast cancers that correlates with clinical outcome. We also found that protein extracts of basal-like cells are sufficient to induce a luminal-to-basal phenotypic switch, implying a trigger of basal-like autoregulatory circuits. We determined that KDM6A might be required for luminal-basal fusions, and we identified EN1, TBX18, and TCF4 as candidate transcriptional regulators of the luminal-to-basal switch. Our findings highlight the remarkable epigenetic plasticity of breast cancer cells.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Su
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute Boston, MA 02215, USA; BBS Program, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Ashim
authors.initials: A
authors.lastname: Subedee
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute Boston, MA 02215, USA.
authors.forename: Noga
authors.initials: N
authors.lastname: Bloushtain-Qimron
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Virginia
authors.initials: V
authors.lastname: Savova
authors.affiliation: Department of Systems Biology, Technical University of Denmark, 2800 Kongens Lyngby, Denmark.
authors.forename: Marcin
authors.initials: M
authors.lastname: Krzystanek
authors.affiliation: Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute Boston, MA 02215, USA.
authors.forename: Lewyn
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Andriy
authors.initials: A
authors.lastname: Marusyk
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute Boston, MA 02215, USA; BBS Program, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Doris P
authors.initials: DP
authors.lastname: Tabassum
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute Boston, MA 02215, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Zak
authors.affiliation: Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Mary Jo
authors.initials: MJ
authors.lastname: Flacker
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute Boston, MA 02215, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jessica J
authors.initials: JJ
authors.lastname: Lin
authors.affiliation: Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Saraswati
authors.initials: S
authors.lastname: Sukumar
authors.affiliation: Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan.
authors.forename: Hiromu
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute Boston, MA 02215, USA.
authors.forename: Henry
authors.initials: H
authors.lastname: Long
authors.affiliation: Department of Systems Biology, Technical University of Denmark, 2800 Kongens Lyngby, Denmark; Children's Hospital, Boston, MA 02115, USA.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Szallasi
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Gimelbrant
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan. Electronic address: reomaru@sapmed.ac.jp.
authors.forename: Reo
authors.initials: R
authors.lastname: Maruyama
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; BBS Program, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; The Broad Institute, Cambridge, MA 02138, USA. Electronic address: kornelia_polyak@dfci.harvard.edu.
authors.forename: Kornelia
authors.initials: K
authors.lastname: Polyak
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D002459:Cell Fusion / Q000379:methods; D045744:Cell Line, Tumor; D057890:Epigenomics; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000235:genetics; D006801:Humans; D061986:MCF-7 Cells; D011401:Promoter Regions, Genetic; D014157:Transcription Factors
chemical_list: C496499:FOXA1 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; D014157:Transcription Factors