Loss of CDH1 and Pten accelerates cellular invasiveness and angiogenesis in the mouse uterus.

E-cadherin (CDH1) is a cell adhesion molecule that coordinates key morphogenetic processes regulating cell growth, cell proliferation, and apoptosis. Loss of CDH1 is a trademark of the cellular event epithelial to mesenchymal transition, which increases the metastatic potential of malignant cells. PTEN is a tumor-suppressor gene commonly mutated in many human cancers, including endometrial cancer. In the mouse uterus, ablation of Pten induces epithelial hyperplasia, leading to endometrial carcinomas. However, loss of Pten alone does not affect longevity until around 5 mo. Similarly, conditional ablation of Cdh1 alone does not predispose mice to cancer. In this study, we characterized the impact of dual Cdh1 and Pten ablation (Cdh1(d/d) Pten(d/d)) in the mouse uterus. We observed that Cdh1(d/d) Pten(d/d) mice died at Postnatal Days 15-19 with massive blood loss. Their uteri were abnormally structured with curly horns, disorganized epithelial structure, and increased cell proliferation. Co-immunostaining of KRT8 and ACTA2 showed invasion of epithelial cells into the myometrium. Further, the uteri of Cdh1(d/d) Pten(d/d) mice had prevalent vascularization in both the endometrium and myometrium. We also observed reduced expression of estrogen and progesterone receptors, loss of cell adherens, and tight junction molecules (CTNNB1 and claudin), as well as activation of AKT in the uteri of Cdh1(d/d) Pten(d/d) mice. However, complex hyperplasia was not found in the uteri of Cdh1(d/d) Pten(d/d) mice. Collectively, these findings suggest that ablation of Pten with Cdh1 in the uterus accelerates cellular invasiveness and angiogenesis and causes early death.

CDH1 is essential for endometrial differentiation, gland development, and adult function in the mouse uterus.

CDH1 is a cell-cell adhesion molecule expressed in the epithelium to coordinate key morphogenetic processes, establish cell polarity, and regulate epithelial differentiation and proliferation. To determine the role of CDH1 in the mouse uterus, Cdh1 was conditionally ablated by crossing Pgr-Cre and Cdh1-flox mice, and the phenotype was characterized. We found that loss of Cdh1 results in a disorganized cellular structure of the epithelium and ablation of endometrial glands in the neonatal uterus. Cdh1(d/d) mice lost adherens junctions (CTNNB1 and CTNNA1) and tight junctions (claudin, occludin, and ZO-1 proteins) in the neonatal uterus, leading to loss of epithelial cell-cell interaction. Ablation of Cdh1 induced abnormal epithelial proliferation and massive apoptosis, and disrupted Wnt and Hox gene expression in the neonatal uterus. Although the uteri of Cdh1(d/d) mice did not show any myometrial defects, ablation of Cdh1 inhibited expression of epithelial (cytokeratin 8) and stromal (CD10) markers. Cdh1(d/d) mice were infertile because of defects during implantation and decidualization. Furthermore, we showed in the model of conditional ablation of both Cdh1 and Trp53 in the uterus that interrupting cell cycle regulation through the loss of Cdh1 leads to abnormal uterine development. The uteri of Cdh1(d/d) Trp53(d/d) mice exhibited histological features of endometrial carcinomas with myometrial invasion. Collectively, these findings suggest that CDH1 has an important role in structural and functional development of the uterus as well as adult uterine function. CDH1 has a capacity to control cell fate by altering directional cell proliferation and apoptosis.

Periareolar injection for localization of sentinel nodes in breast cancer patients.

The goal of this study was to evaluate the periareolar injection of technetium 99m sulfur colloid to identify axillary sentinel nodes and compare the number of sentinel lymph nodes identified with preoperative lymphoscintigraphy to intraoperative biopsy using a handheld gamma probe. A total of 104 consecutive patients diagnosed with invasive breast cancer participated in this prospective study, with 81 patients receiving an intradermal periareolar injection and 23 patients receiving an intradermal peritumoral injection of filtered technetium 99m sulfur colloid. Preoperative lymphoscintigraphy was performed for sentinel node mapping and localization. In addition to selective sentinel node biopsy, axillary dissection was performed on all patients to determine false-negative rates. Routine histologic staining was performed on all identified nodes, along with immunohistochemical staining of sentinel nodes negative on initial routine staining. With an intradermal periareolar injection, the sentinel node identification rate was 91.4% (74/81), axillary metastatic rate 35.1% (26/74), sentinel node positive only 61.5% (16/26), and false negative 3.8% (1/26). With an intradermal peritumoral injection, the sentinel node identification rate was 91.3% (21/23), axillary metastatic rate 42.9% (9/21), sentinel node positive only 88.9% (8/9), and false negative 0% (0/9). A total of 241 sentinel nodes were identified with biplanar lymphoscintigraphy and 173 sentinel nodes were harvested during surgery, yielding a 28.2% increase in sentinel nodes identified with lymphoscintigraphy. This study demonstrates that intradermal periareolar injection of filtered technetium 99m sulfur colloid is successful in identifying axillary sentinel nodes with a low false-negative rate. Preoperative lymphoscintigraphy aids in the identification and surgical planning of sentinel node biopsy and provides an objective measure of surgical performance.