Role of Neural (N)-Cadherin in Breast Cancer Cell Stemness and Dormancy in the Bone Microenvironment

Abstract

Breast cancer cells that interact with spindle-shaped N-Cadherin+ Osteoblasts (SNOs) are recognised to become dormant through a Notch2-dependent mechanism. We found that Notch2High human BrCa MDA-MB231 (MDA) cells also expressed high level of N-Cadherin. This prompted us to hypothesize that N-Cadherin could have a role in MDA-SNO interaction. Of note, the expression of N-Cadherin in MDA cells reduced tumour incidence and bone osteolysis in BrCa mouse model. Moreover, similarly to Notch2High MDA cells, the N-CadherinHigh MDA cells revealed a high expression of the canonical Haematopoietic Stem cell (HSC) markers, suggesting an HSC mimicry, associated with higher ability to form mammospheres. Interestingly, N-CadherinHigh MDA cells showed greater capacity to adhere to SNOs, while the inhibition of SNO-mediating MDA cell proliferation was unremarkable. To investigate whether these features were shared by mouse BrCa, we used the 4T1 cell line in which N-Cadherin expression was abolished and then rescued. At variance with MDA cells, 4T1 cells expressing N-Cadherin revealed that the latter was associated with a lower expression of the HSC marker, Cxcr4, along with a lower capacity to form mammospheres. Furthermore, the rescue of N-Cadherin expression increased cell-cell adhesion and reduced proliferation of 4T1 cells when they were co-plated with SNOs. In conclusion, we demonstrated that: (i) N-CadherinHigh and Notch2High MDA cells showed similar HSC mimicry and dormancy features; (ii) N-Cadherin mediated BrCa-SNO adhesion; (iii) N-Cadherin had a positive Notch2-dependent role on SNO-induced dormancy and HSC mimicry in MDA cells, and a negative role in 4T1 cell stemness and HSC mimicry.

Keywords

• BrCa dormancy
• cancer stem cells
• HSC-mimicry
• osteoblasts
• endosteal niche
• bone microenvironment