CDH3/P-cadherin overexpression in breast carcinomas: its regulatory mechanisms, the role in cell invasion, and the association with cancer stem cell properties

One of the most basic characteristics of cancer cells is the loss of cell-cell adhesion and acquirement of invasive properties. During cancer progression, the regulation and expression of cell-cell adhesion molecules (like cadherins) play a pivotal role. In most invasive tumors, E-cadherin is downregulated and N-cadherin is de novo expressed (known as epithelial-to-mesenchymal transition). However, in some invasive carcinomas, E-cadherin expression is maintained, with the concomitant de novo expression of another cadherin – P-cadherin. Their co-expression occurs frequently in breast carcinomas, which show a worst patient prognosis when compared with patients harboring tumors with loss of E-cadherin as single event. In the last ten years, our group has been mainly interested in understanding the role of P-cadherin overexpression in cancer cells, as well as the gene regulatory mechanisms behind its aberrant expression.

P-cadherin has been extensively studied concerning its function and prognostic value in breast cancer. Its overexpression has been identified in 30% of invasive carcinomas, being highly associated with proliferative lesions of high histological grade and decreased patient survival. Recently, we showed that P-cadherin overexpression confers an invasive capacity to breast cancer cells, inducing the secretion of MMPs, which are responsible by the cleavage of its extracellular domain, giving rise to a P-cadherin soluble form. We proved that this fragment is a pro-invasive factor, which needs to be inhibited to render cancer cells non-invasive.

Still, we identified the intracellular signaling pathway that regulates and activates the P-cadherin (CDH3) gene promoter, inducing P-cadherin overexpression in breast cancer cells. We found that an antiestrogen is able to increase CDH3 promoter activity, as well as to induce activating histone epigenetic modifications at putative C/EBPβ binding sites in the CDH3 gene promoter. We showed, for the first time, that C/EBPβ is able to regulate P-cadherin overexpression.

Furthermore, our recent data supports the idea that P-cadherin has a role in cancer stem cell biology. We found that breast cancer cell lines, presenting the highest levels of P-cadherin, show the highest expression of the stem cell markers CD49f, CD44 and CD24, as well as ALDH1 activity. Importantly, we reproduced these results in primary tumors, where we found that P-cadherin overexpression occurs in breast carcinomas with a cancer stem cell phenotype (CD44⁺CD24^-/low) and ALDH1 expression. These results are now being experimentally addressed by mammosphere, 2D and 3D culture in vitro assays, to be then confirmed in vivo.

In conclusion, our results open new avenues in breast cancer treatment, since P-cadherin is likely to be a good therapeutic target for invasive carcinomas overexpressing this protein. Scientifically, our studies will help to understand better the pathogenesis of breast cancer and other cancer models involving cadherin’s alterations.