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

doi:10.1016/j.celrep.2023.113564

Heterogeneity and transcriptional drivers of triple-negative breast cancer

Cell Rep. 2023 Dec 26;42(12):113564. doi: 10.1016/j.celrep.2023.113564. Epub 2023 Dec 14.

Authors

Bojana Jovanović¹, Daniel Temko², Laura E Stevens¹, Marco Seehawer¹, Anne Fassl³, Katherine Murphy⁴, Jayati Anand⁴, Kodie Garza⁴, Anushree Gulvady¹, Xintao Qiu⁵, Nicholas W Harper⁴, Veerle W Daniels⁴, Huang Xiao-Yun⁴, Jennifer Y Ge⁶, Maša Alečković¹, Jason Pyrdol⁷, Kunihiko Hinohara¹, Shawn B Egri⁸, Malvina Papanastasiou⁸, Raga Vadhi⁵, Alba Font-Tello⁹, Robert Witwicki¹, Guillermo Peluffo¹, Anne Trinh¹, Shaokun Shu¹, Benedetto Diciaccio⁴, Muhammad B Ekram¹, Ashim Subedee⁴, Zachary T Herbert¹⁰, Kai W Wucherpfennig⁷, Anthony G Letai¹, Jacob D Jaffe⁸, Piotr Sicinski³, Myles Brown¹¹, Deborah Dillon¹², Henry W Long¹³, Franziska Michor¹⁴, Kornelia Polyak¹⁵

Affiliations

¹ 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.
² 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.
³ Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
⁴ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁵ Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁶ 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.
⁷ 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.
⁸ The Eli and Edythe L. Broad Institute, Cambridge, MA 02142, USA.
⁹ Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
¹⁰ Department of Molecular Biology Core Facility, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
¹¹ 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.
¹² Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
¹³ 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.
¹⁴ 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. Electronic address: michor@jimmy.harvard.edu.
¹⁵ 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. Electronic address: kornelia_polyak@dfci.harvard.edu.

Abstract

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.

Keywords: CP: Cancer; triple-negative breast cancer; tumor heterogeneity.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Gene Expression Regulation, Neoplastic
Homeodomain Proteins / metabolism
Humans
Transcription Factors / metabolism
Triple Negative Breast Neoplasms* / pathology

Substances

Transcription Factors
PRRX1 protein, human
Homeodomain Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding