'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: Hanan Abu-Tayeh, Keren Weidenfeld, Alisa Zhilin-Roth, Sagi Schif-Zuck, Sonja Thaler, Cristina Cotarelo, Tuan Z Tan, Jean P Thiery, Jeffrey E Green, Geula Klorin, Edmond Sabo, Jonathan P Sleeman, Maty Tzukerman, Dalit Barkan
• Journal: Cell death & disease (Cell Death Dis) Vol. 7 Issue 12 Pg. e2491 (12 01 2016) ISSN: 2041-4889 [Electronic] England
• PMID: 27906177 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Integrin alphaVbeta3
• NOTCH4 protein, human
• Proto-Oncogene Proteins
• Receptor, Notch4
• Receptors, Notch

Topics

• Acinar Cells (metabolism, pathology)
• Basement Membrane (metabolism)
• Breast Neoplasms (pathology)
• Cell Differentiation
• Cell Line, Tumor
• Cell Proliferation
• Down-Regulation
• Embryonic Stem Cells (metabolism)
• Female
• Gene Knockdown Techniques
• Humans
• Hyperplasia
• Integrin alphaVbeta3 (metabolism)
• MCF-7 Cells
• Neoplastic Stem Cells (metabolism, pathology)
• Organoids (metabolism, pathology)
• Phenotype
• Proto-Oncogene Proteins (metabolism)
• Receptor, Notch4
• Receptors, Notch (metabolism)
• Signal Transduction
• Spheroids, Cellular (metabolism, pathology)
• Teratoma (pathology)