title: 'Normalizing' the malignant phenotype of luminal breast cancer cells via alpha(v)beta(3)-integrin.
abstract: Reestablishing tissue organization of breast cancer cells into acini was previously shown to override their malignant phenotype. In our study, we demonstrate that alpha(v)beta(3) integrin (Int-αvβ3), previously shown to play a role in cancer progression, promoted differentiation and growth arrest of organoids derived from luminal A breast cancer cells grown in their relevant three-dimensional microenvironment. These organoids differentiated into normal-like acini resembling a benign stage of breast tissue. Likewise, we demonstrate that Int-αvβ3 is selectively expressed in the epithelium of the benign stage of breast tissues, and is lost during the early stages of luminal A breast cancer progression. Notably, the organoids' reversion into normal-like acini was mediated by cancer luminal progenitor-like cells expressing both EpCAMhighCD49flowCD24+and Int-αvβ3. Furthermore, downregulation of Notch4 expression and downstream signaling was shown to mediate Int-αvβ3-induced reversion. Intriguingly, when luminal A breast cancer cells expressing Int-αvβ3 were injected into a humanized mouse model, differentiated tumors developed when compared with that generated by control cells. Hence, our data suggest that promoting differentiation of luminal A breast cancer cells by signaling emanating from Int-αvβ3 can potentially promote 'normalization' of their malignant phenotype and may prevent the malignant cells from progressing.
authors.affiliation: Department of Human Biology, University of Haifa, Haifa, Israel.
authors.forename: Hanan
authors.initials: H
authors.lastname: Abu-Tayeh
authors.affiliation: Department of Human Biology, University of Haifa, Haifa, Israel.
authors.forename: Keren
authors.initials: K
authors.lastname: Weidenfeld
authors.affiliation: Department of Human Biology, University of Haifa, Haifa, Israel.
authors.forename: Alisa
authors.initials: A
authors.lastname: Zhilin-Roth
authors.affiliation: Department of Human Biology, University of Haifa, Haifa, Israel.
authors.forename: Sagi
authors.initials: S
authors.lastname: Schif-Zuck
authors.affiliation: Medical Faculty Mannheim, Centre for Biomedicine and Medical Technology Mannheim (CBTM), University of Heidelberg, Mannheim, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Thaler
authors.affiliation: Department of Pathology, University Medical Center Mainz, Langenbeckstr, Mainz, Germany.
authors.forename: Cristina
authors.initials: C
authors.lastname: Cotarelo
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: Tuan Z
authors.initials: TZ
authors.lastname: Tan
authors.affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.|Institute of Molecular and Cell Biology, A*STAR, Singapore, Singapore.
authors.forename: Jean P
authors.initials: JP
authors.lastname: Thiery
authors.affiliation: Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Green
authors.affiliation: Department of Pathology, Rambam Medical Center, Haifa, Israel.
authors.forename: Geula
authors.initials: G
authors.lastname: Klorin
authors.affiliation: Department of Pathology, Rambam Medical Center, Haifa, Israel.
authors.forename: Edmond
authors.initials: E
authors.lastname: Sabo
authors.affiliation: Medical Faculty Mannheim, Centre for Biomedicine and Medical Technology Mannheim (CBTM), University of Heidelberg, Mannheim, Germany.|Karlsruhe Institute of Technology (KIT), Campus Nord, Institut für Toxikologie und Genetik, Karlsruhe, Germany.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Sleeman
authors.affiliation: Rappaport Faculty of Medicine and Research Institute, Technion - Israel Institute of Technology, Haifa, Israel.
authors.forename: Maty
authors.initials: M
authors.lastname: Tzukerman
authors.affiliation: Department of Human Biology, University of Haifa, Haifa, Israel.
authors.forename: Dalit
authors.initials: D
authors.lastname: Barkan
mesh_terms: D061354:Acinar Cells / Q000378:metabolism / Q000473:pathology; D001485:Basement Membrane / Q000378:metabolism; D001943:Breast Neoplasms / Q000473:pathology*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015536:Down-Regulation; D053595:Embryonic Stem Cells / Q000378:metabolism; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D006965:Hyperplasia; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D061986:MCF-7 Cells; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D009940:Organoids / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D000074562:Receptor, Notch4; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction; D018874:Spheroids, Cellular / Q000378:metabolism / Q000473:pathology; D013724:Teratoma / Q000473:pathology
chemical_list: D039302:Integrin alphaVbeta3; C106075:NOTCH4 protein, human; D011518:Proto-Oncogene Proteins; D000074562:Receptor, Notch4; D051880:Receptors, Notch