P-Cadherin Linking Breast Cancer Stem Cells and Invasion: A Promising Marker to Identify an "Intermediate/Metastable" EMT State

Abstract

Epithelial-mesenchymal transition (also known as EMT) is a fundamental mechanism occurring during embryonic development and tissue differentiation, being also crucial for cancer progression. Actually, the EMT program contributes to the dissemination of cancer cells from solid tumors and to the formation of micro-metastasis that subsequently develop into clinically detectable metastases. Besides being a process that is defined by the progressive loss of epithelial cell characteristics and the acquisition of mesenchymal features, EMT has also been implicated in therapy resistance, immune escape, and maintenance of cancer stem cell properties, such as self-renewal capacity. However, the majority of the studies usually neglect the progressive alterations occurring during intermediate EMT states, which imply a range of phenotypic cellular heterogeneity that can potentially generate more metastable and plastic tumor cells. In fact, few studies have tried to identify these transitory states, partly due to the current lack of a detailed understanding of EMT, as well as of reliable readouts for its progression. Herein, a brief review of evidences is presented, showing that P-cadherin expression, which has been already identified as a breast cancer stem cell marker and invasive promoter, is probably able to identify an intermediate EMT state associated with a metastable phenotype. This hypothesis is based on our own work, as well as on the results described by others, which suggest the use of P-cadherin as a promising EMT marker, clearly functioning as an important clinical prognostic factor and putative therapeutic target in breast carcinogenesis.

Keywords: EMT transition; P-cadherin; breast cancer; metastable phenotype; metastasis.

Figure 1

Hallmarks of P-cadherin function in breast cancer cells. P-cadherin overexpressing cells acquire features that give them an advantage to survive in a hostile environment leading to an invasive and tumorigenic phenotype of breast cancer cells. P-cadherin expression affects cell–cell adhesion, since it disrupts the normal suppressor function of E-cadherin, by decreasing the interaction between E-cadherin and intracellular catenins. Overexpression of this protein in breast cancer cells promotes an increase in cell migration and cell invasion, being able to provoke the secretion of pro-invasive factors, such as MMP1 and MMP2, which then lead to P-cadherin ectodomain cleavage (sP-cad) that also has pro-invasive activity by itself. Moreover, P-cadherin expression mediates cancer stem cell properties, conferring resistance to x-ray-induced cell death and being related with a hypoxic, glycolytic, and acid-resistant phenotype in breast cancer cells.

Figure 2

Proposed model of P-cadherin expression in EMT progression. Schematic representation adapted from Schmitt et al. (54) of the different types of breast cancer in what concerns cancer stem cells proteins (CD24, CD44, CD49f, and ALDH1), EMT markers, and P-cadherin expression during EMT progression. A decrease of epithelial proteins with a concomitant increase in mesenchymal markers is observed during the transition from an epithelial to a mesenchymal phenotype. During this process, we hypothesize that P-cadherin expression is in very low levels in both full epithelial and full mesenchymal states; however, an increased expression can be seen in the metastable and intermediate states of EMT.