title: Integrin-β4 identifies cancer stem cell-enriched populations of partially mesenchymal carcinoma cells.
abstract: Neoplastic cells within individual carcinomas often exhibit considerable phenotypic heterogeneity in their epithelial versus mesenchymal-like cell states. Because carcinoma cells with mesenchymal features are often more resistant to therapy and may serve as a source of relapse, we sought to determine whether such cells could be further stratified into functionally distinct subtypes. Indeed, we find that a basal epithelial marker, integrin-β4 (ITGB4), can be used to enable stratification of mesenchymal-like triple-negative breast cancer (TNBC) cells that differ from one another in their relative tumorigenic abilities. Notably, we demonstrate that ITGB4+cancer stem cell (CSC)-enriched mesenchymal cells reside in an intermediate epithelial/mesenchymal phenotypic state. Among patients with TNBC who received chemotherapy, elevated ITGB4 expression was associated with a worse 5-year probability of relapse-free survival. Mechanistically, we find that the ZEB1 (zinc finger E-box binding homeobox 1) transcription factor activity in highly mesenchymal SUM159 TNBC cells can repress expression of the epithelial transcription factor TAp63α (tumor protein 63 isoform 1), a protein that promotes ITGB4 expression. In addition, we demonstrate that ZEB1 and ITGB4 are important in modulating the histopathological phenotypes of tumors derived from mesenchymal TNBC cells. Hence, mesenchymal carcinoma cell populations are internally heterogeneous, and ITGB4 is a mechanistically driven prognostic biomarker that can be used to identify the more aggressive subtypes of mesenchymal carcinoma cells in TNBC. The ability to rapidly isolate and mechanistically interrogate the CSC-enriched, partially mesenchymal carcinoma cells should further enable identification of novel therapeutic opportunities to improve the prognosis for high-risk patients with TNBC.
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142.
authors.forename: Brian
authors.initials: B
authors.lastname: Bierie
authors.affiliation: Department of Biology, Brown University, Providence, RI 02912.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Pierce
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Kroeger
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Stover
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142.
authors.forename: Diwakar R
authors.initials: DR
authors.lastname: Pattabiraman
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142.
authors.forename: Prathapan
authors.initials: P
authors.lastname: Thiru
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142.
authors.forename: Joana
authors.initials: J
authors.lastname: Liu Donaher
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142.
authors.forename: Ferenc
authors.initials: F
authors.lastname: Reinhardt
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142.
authors.forename: Christine L
authors.initials: CL
authors.lastname: Chaffer
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Keckesova
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142; weinberg@wi.mit.edu.|Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142.|Ludwig Center for Molecular Oncology, Massachusetts Institute of Technology, Cambridge, MA 02139.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Weinberg
mesh_terms: D002277:Carcinoma / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D039663:Integrin beta4 / Q000235:genetics / Q000378:metabolism*; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D011379:Prognosis; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D000071799:Zinc Finger E-box-Binding Homeobox 1 / Q000235:genetics / Q000378:metabolism
chemical_list: C059834:ITGB4 protein, human; D039663:Integrin beta4; C115051:TP63 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000071799:Zinc Finger E-box-Binding Homeobox 1
keywords: EMT; ITGB4; cancer; heterogeneity; mesenchymal