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

Autor: Cristina Cotarelo, Dalit Barkan, Jean P. Thiery, Tuan Zea Tan, Maty Tzukerman, Edmond Sabo, Jeffrey Green, Hanan Abu-Tayeh, Sagi Schif-Zuck, Geula Klorin, Keren Weidenfeld, Jonathan P. Sleeman, Sonja Thaler, Alisa Zhilin-Roth
Rok vydání: 2016
Předmět:
0301 basic medicine
Cancer Research
Pathology
medicine.medical_specialty
Cellular pathology
Alpha-v beta-3
Cellular differentiation
Immunology
Down-Regulation
Breast Neoplasms
Acinar Cells
Biology
Basement Membrane
03 medical and health sciences
Cellular and Molecular Neuroscience
chemistry.chemical_compound
0302 clinical medicine
Breast cancer
Cell Line
Tumor
Proto-Oncogene Proteins
Spheroids
Cellular
medicine
Humans
Receptor
Notch4
Embryonic Stem Cells
Cell Proliferation
Integrin alphaVbeta3
Hyperplasia
Receptors
Notch
Teratoma
Cancer
Cell Differentiation
Cell Biology
medicine.disease
Organoids
030104 developmental biology
Phenotype
chemistry
030220 oncology & carcinogenesis
Gene Knockdown Techniques
Humanized mouse
Cancer research
MCF-7 Cells
Neoplastic Stem Cells
Female
Original Article
Signal Transduction
Zdroj: Cell Death & Disease
ISSN: 2041-4889
Popis: 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.
Databáze: OpenAIRE
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