Cell Reports (Dec 2023)
Heterogeneity and transcriptional drivers of triple-negative breast cancer
- Bojana Jovanović,
- Daniel Temko,
- Laura E. Stevens,
- Marco Seehawer,
- Anne Fassl,
- Katherine Murphy,
- Jayati Anand,
- Kodie Garza,
- Anushree Gulvady,
- Xintao Qiu,
- Nicholas W. Harper,
- Veerle W. Daniels,
- Huang Xiao-Yun,
- Jennifer Y. Ge,
- Maša Alečković,
- Jason Pyrdol,
- Kunihiko Hinohara,
- Shawn B. Egri,
- Malvina Papanastasiou,
- Raga Vadhi,
- Alba Font-Tello,
- Robert Witwicki,
- Guillermo Peluffo,
- Anne Trinh,
- Shaokun Shu,
- Benedetto Diciaccio,
- Muhammad B. Ekram,
- Ashim Subedee,
- Zachary T. Herbert,
- Kai W. Wucherpfennig,
- Anthony G. Letai,
- Jacob D. Jaffe,
- Piotr Sicinski,
- Myles Brown,
- Deborah Dillon,
- Henry W. Long,
- Franziska Michor,
- Kornelia Polyak
Affiliations
- Bojana Jovanović
- 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
- Daniel Temko
- Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA
- Laura E. Stevens
- 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
- Marco Seehawer
- 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
- Anne Fassl
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
- Katherine Murphy
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
- Jayati Anand
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
- Kodie Garza
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
- Anushree Gulvady
- 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
- Xintao Qiu
- Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA
- Nicholas W. Harper
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
- Veerle W. Daniels
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
- Huang Xiao-Yun
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
- Jennifer Y. Ge
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard-MIT Division of Health Sciences and Technology, Harvard Medical School, Boston, MA 02115, USA
- Maša Alečković
- 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
- Jason Pyrdol
- Departments of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Departments of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA
- Kunihiko Hinohara
- 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
- Shawn B. Egri
- The Eli and Edythe L. Broad Institute, Cambridge, MA 02142, USA
- Malvina Papanastasiou
- The Eli and Edythe L. Broad Institute, Cambridge, MA 02142, USA
- Raga Vadhi
- Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA
- Alba Font-Tello
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
- Robert Witwicki
- 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
- Guillermo Peluffo
- 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
- Anne Trinh
- 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
- Shaokun Shu
- 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
- Benedetto Diciaccio
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
- Muhammad B. Ekram
- 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
- Ashim Subedee
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
- Zachary T. Herbert
- Department of Molecular Biology Core Facility, Dana-Farber Cancer Institute, Boston, MA 02215, USA
- Kai W. Wucherpfennig
- Departments of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Departments of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA
- Anthony G. Letai
- 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
- Jacob D. Jaffe
- The Eli and Edythe L. Broad Institute, Cambridge, MA 02142, USA
- Piotr Sicinski
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
- Myles Brown
- 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; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02115, USA
- Deborah Dillon
- Department of Pathology, Brigham and Women’s Hospital, Boston, MA 02115, USA
- Henry W. Long
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA
- Franziska Michor
- Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; The Eli and Edythe L. Broad Institute, Cambridge, MA 02142, USA; Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02115, USA; Center for Cancer Evolution, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Corresponding author
- Kornelia Polyak
- 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; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA; The Eli and Edythe L. Broad Institute, Cambridge, MA 02142, USA; Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02115, USA; Center for Cancer Evolution, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Corresponding author
- Journal volume & issue
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Vol. 42,
no. 12
p. 113564
Abstract
Summary: Triple-negative breast cancer (TNBC) is a heterogeneous disease with limited treatment options. To characterize TNBC heterogeneity, we defined transcriptional, epigenetic, and metabolic subtypes and subtype-driving super-enhancers and transcription factors by combining functional and molecular profiling with computational analyses. Single-cell RNA sequencing revealed relative homogeneity of the major transcriptional subtypes (luminal, basal, and mesenchymal) within samples. We found that mesenchymal TNBCs share features with mesenchymal neuroblastoma and rhabdoid tumors and that the PRRX1 transcription factor is a key driver of these tumors. PRRX1 is sufficient for inducing mesenchymal features in basal but not in luminal TNBC cells via reprogramming super-enhancer landscapes, but it is not required for mesenchymal state maintenance or for cellular viability. Our comprehensive, large-scale, multiplatform, multiomics study of both experimental and clinical TNBC is an important resource for the scientific and clinical research communities and opens venues for future investigation.
