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 EpCAM high CD49f low CD24 + 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.
Bibliographical noteFunding Information:
This research was supported by the British and Swiss friends of University of Haifa (DB) and by grants from the Daniel M. Soref Charitable Trust, Skirball Foundation, Richard D. Satell Foundation, Sohnis and Forman families and the Israel Science Foundation (Grant No. 62/10 MT).
© 2016 The Author (S).
ASJC Scopus subject areas
- Cellular and Molecular Neuroscience
- Cell Biology
- Cancer Research