Interaction of E-cadherin and PTEN Regulates Morphogenesis and Growth Arrest in Human Mammary Epithelial Cells

Abstract

Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is a dual-function phosphatase with tumor suppressor function compromised in a wide spectrum of cancers. Because tissue polarity and architecture are crucial modulators of normal and malignant behavior, we postulated that PTEN may play a role in maintenance of tissue integrity. We used two nonmalignant human mammary epithelial cell lines that form polarized, growth-arrested structures (acini) when cultured in three-dimensional laminin-rich extracellular matrix gels (lrECM). As acini begin to form, PTEN accumulates both in the cytoplasm and at cell-cell contacts where it colocalizes with the E-cadherin/B-catenin complex. Reduction of PTEN levels by shRNA in lrECM prevents formation of organized breast acini and disrupts growth arrest. Importantly, disruption of acinar polarity and cell-cell contact by E-cadherin function-blocking antibodies reduces endogenous PTEN protein levels and inhibits its accumulation at cell-cell contacts. Conversely, in Skbr-3 breast cancer cells lacking endogenous E-cadherin expression, exogenous introduction of E-cadherin gene causes induction of PTEN expression and its accumulation at sites of cell interactions. These studies provide evidence that E-cadherin regulates both the PTEN protein levels and its recruitment to cell-cell junctions in three-dimensional lrECM, indicating a dynamic reciprocity between architectural integrity and the levels and localization of PTEN. This interaction thus seems to be a critical integrator of proliferative and morphogenetic signaling in breast epithelial cells. [Cancer Res 2009;69(10):4545-52]

E-cadherin inhibits tumor cell growth by suppressing PI3K/Akt signaling via β-catenin-Egr1-mediated PTEN expression

“…In agreement, recent studies in breast cancer cells have implicated E-cadherin-mediated cell-cell adhesion in the regulation of PTEN. Specifically, exogenous expression of E-cadherin increases, whereas function-blocking E-cadherin antibody or siRNA-mediated knockdown reduces, PTEN protein levels Fournier et al, 2009). PTEN transcription is regulated by numerous transcription factors.…”

“…It has been shown that PTEN transcription can be transactivated by early growth response gene 1 (Egr1), which binds directly to a consensus Egr1-binding motif in the PTEN promoter (Virolle et al, 2001). Recent studies suggest that E-cadherin modulates PTEN levels in breast cancer cells Fournier et al, 2009); however, the exact mechanism by which E-cadherin regulates PTEN levels is unclear.…”

Integration column: microwell arrays for mammalian cell culture

“…43 Further, the reduced expression of proteins such as Cadherins that mediate cell-cell contacts can correlate with tumor formation and progression, 44 conceivably through the loss of epithelial integrity and polarization. 45 Therefore, an augmentation of microwell platforms towards a mimickry of this cell-cell crosstalk ( Fig. 2A) would be of great benefit for many basic biological studies.…”

Significant elevation of CLDN16 and HAPLN3 gene expression in human breast cancer

“…We suggested that upexpression of HAPLN3 could contribute to the promotion of cell proliferation, migration, and angiogenesis by cooperation with versican or hyaluronan. Moreover, overexpression of CLDN16 dominated the alteration of cell polarity in breast cancer (9,18,31), and mutual up-expression of both CLDN16 and HAPLN3 could contribute to the development of breast cancer, although those mechanisms require further clarification.…”

“…During cancer development, the destruction of tight junctions (8), as well as the deprivation of cell polarity (9,10) and increased cell mobility (11,12), contribute to cancer cell proliferation, invasion, and metastasis, and a poor prognosis. Claudin-16 (CLDN16), a member of the claudins family, is a tight junction protein and plays important roles in the maintenance of cell polarity, cellular arrangement, adhesion, paracellular transport, and ionic permeability of various epithelia (13)(14)(15)(16).…”