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Cell Death Dis. 2016 Dec 1;7(12):e2491. doi: 10.1038/cddis.2016.387.

'Normalizing' the malignant phenotype of luminal breast cancer cells via alpha(v)beta(3)-integrin.

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Department of Human Biology, University of Haifa, Haifa, Israel.
Medical Faculty Mannheim, Centre for Biomedicine and Medical Technology Mannheim (CBTM), University of Heidelberg, Mannheim, Germany.
Department of Pathology, University Medical Center Mainz, Langenbeckstr, Mainz, Germany.
Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
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.
Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, MD, USA.
Department of Pathology, Rambam Medical Center, Haifa, Israel.
Karlsruhe Institute of Technology (KIT), Campus Nord, Institut für Toxikologie und Genetik, Karlsruhe, Germany.
Rappaport Faculty of Medicine and Research Institute, Technion - Israel Institute of Technology, Haifa, Israel.


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.

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