Expression and Functional Role of E- and P-Cadherins in Mouse Mammary Ductal Morphogenesis and Growth

Abstract

Mammary ducts, and the highly mitotic terminal end buds from which they are derived, consist of two layers of ectodermally derived epithelium, forming a tube-within-a-tube structure. We investigated the role of Ca(2+)-dependent cell-cell adhesion molecules in maintaining the integrity of these layers. Immunostaining showed abundant E-cadherin on the lateral membranes of end bud body cells and ductal lumenal cells, but no P-cadherin. The basally located cap cells and their differentiated descendants, the ductal myoepithelial cells, displayed only P-cadherin. We investigated the functional significance of this pattern of cadherin expression in situ by surgically implanting small, slow-release plastic implants releasing function-blocking antibodies. End buds exposed to a monoclonal antibody to E-cadherin showed disruption of the body epithelium, with epithelial cells floating freely in the lumen. Epithelial DNA synthesis, which is normally very high in these growth buds, abruptly declined. That this reduction in growth was not due to cell damage was shown by spontaneous reaggregation of the cells into a normal epithelium, with resumption of DNA synthesis, when the blocking antibody was depleted. A monoclonal antibody to P-cadherin had no effect on the lumenal layer but partially disrupted the basally located cap cell layer. These data indicate that spatially selective expression of E- and P-cadherins is required for mammary tissue integrity, which is in turn a prerequisite for normal rates of DNA synthesis.

Loss of cyclin D1 in concert with deregulated estrogen receptor α expression induces DNA damage response activation and interrupts mammary gland morphogenesis

“…Since CERM D1À/À TEBs showed large empty luminal spaces and exaggerated subcapsular spaces, the expression patterns of adhesion proteins were investigated. P-cadherin is selectively expressed by cap cells and E-cadherin is expressed only by body cells (Daniel et al, 1995). Immunohistochemical staining of P-and E-cadherin on CERM D1À/À TEBs demonstrated normal expression patterns of these adhesion proteins (Figures 3g-j).…”

The Prognostic Significance of P-Cadherin in Infiltrating Ductal Breast Carcinoma

“…Experimental studies have also suggested a fundamental morphoregulatory role for P-CD during breast development. P-CD expression is characteristic of the stem cells (cap cells), the precursor of myoepithelial cells, which do not express estrogen receptors and have a high proliferation rate and low frequency of apoptosis (7). In addition, P-CD-deficient mice have anomalous mammary gland development (8).…”

Cadherins and the mammary gland

“…Basal to the lumenal epithelial cell layer are myoepithelial cells, which arise from the differentiation of cap cells and play a role in milk extrusion and maintaining the ductal phenotype. Myoepithelial cells interact with the basement membrane and express P-cadherin, but not E-cadherin [Daniel et al, 1995]. Thus, E-cadherin knits together the epithelial cells, whereas P-cadherin knits together the myoepithelial cells.…”

“…E-cadherin disruption in the mammary epithelium results in massive apoptosis at parturition with a concomitant loss of milk production, indicating that E-cadherin is essential for differentiation, epithelial cell survival, and function of the mammary gland [Delmas Boussadia et al, 2002]. In vitro work also supports a critical role for E-cadherin in the function and architecture of the mammary gland [Daniel et al, 1995].…”

“…These cells express E-cadherin [Daniel et al, 1995], as well as associated catenins a-, b-plakoglobin, and p120. Basal to the lumenal epithelial cell layer are myoepithelial cells, which arise from the differentiation of cap cells and play a role in milk extrusion and maintaining the ductal phenotype.…”