Loss of cell polarization and luminal filling of mammary glands are key structural alterations in breast cancer disease. Recent findings support the notion that disruption of cell-polarity mechanisms plays a causal role in tumor initiation thus, implicating a role of cell and tissue polarity mechanisms as potential non-canonical tumor suppressors. We present here for the first time the role of beta 3 -integrin (Intβ3) in promoting the commitment of luminal breast cancer progenitor like cells to differentiate to polarized acini like structure. Our results demonstrate that overexpression of Intβ3, in MCF-7 cells (MCF-7-Intβ3) promoted their reversion to acini like organoids resembling a normal breast tissue, when cultured in the physiological relevant 3 dimensional basement membrane extract (3D BME system). The phenotypic reversion was demonstrated by the generation of acinus like organoids with apicobasal polarity displayed by the apical expression of GM130 and mucin-1 (MUC1), and basal expression of laminin 5. These organoids gradually progressed into spherical lumen containing structures resembling normal breast tissue. Conversely, control MCF-7 cells stably expressing empty vector (MCF-7-vec) did not undergo phenotypic reversion. Intriguingly, this reversion was driven by cancer progenitor like cells derived from non-adherent mammospheres (either expressing CD44-/low CD24high or EpCAMhighCD49flow phenotype) that expressed Intβ3. Whereas, Intβ3- cancer progenitor like cells could not differentiate to acini like structure in the 3D BME system. Therefore, these results suggest that commitment of the cancer luminal progenitor like cells to differentiate is dependent on Intβ3 expression. Finally, we have preliminary results demonstrating that the reversion of MCF-7-Intβ3 cells to a normal like phenotype induced a dormant state depicted by induction of p21 expression and reduction in Ki67 positive cells compared to MCF-7-vec cells.
Hence, these finding exhibits a novel mechanism to reprogram cancer luminal progenitor like cells to differentiate to a normal like acini by inducing the expression of Intβ3. Therefore, promoting such differentiation of luminal breast cancer cells in conjunction to their microenvironment, can potentially promote the normalization of their malignant phenotype.
