Mechanisms of mutant ß-catenin in endometrial cancer progression.

Endometrial carcinoma (EC) is the most diagnosed gynecological malignancy in Western countries. Both incidence and mortality rates of EC have steadily risen in recent years. Despite generally favorable prognoses for patients with the endometrioid type of EC, a subset of patients has been identified with decreased progression-free survival. Patients in this group are distinguished from other endometrioid EC patients by the presence of exon 3 hotspot mutations in CTNNB1, the gene encoding for the ß-catenin protein. ß-catenin is an evolutionarily conserved protein with critical functions in both adherens junctions and Wnt-signaling. The exact mechanism by which exon 3 CTNNB1 mutations drive EC progression is not well understood. Further, the potential contribution of mutant ß-catenin to adherens junctions' integrity is not known. Additionally, the magnitude of worsened progression-free survival in patients with CTNNB1 mutations is context dependent, and therefore the importance of this subset of patients can be obscured by improper categorization. This review will examine the history and functions of ß-catenin, how these functions may change and drive EC progression in CTNNB1 mutant patients, and the importance of this patient group in the broader context of the disease.

Differential roles of factors IX and XI in murine placenta and hemostasis under conditions of low tissue factor.

The intrinsic tenase complex (FIXa-FVIIIa) of the intrinsic coagulation pathway and, to a lesser extent, thrombin-mediated activation of FXI, are necessary to amplify tissue factor (TF)-FVIIa-initiated thrombin generation. In this study, we determined the contribution of murine FIX and FXI to TF-dependent thrombin generation in vitro. We further investigated TF-dependent FIX activation in mice and the contribution of this pathway to hemostasis. Thrombin generation was decreased in FIX- but not in FXI-deficient mouse plasma. Furthermore, injection of TF increased levels of FIXa-antithrombin complexes in both wild-type and FXI-/- mice. Genetic studies were used to determine the effect of complete deficiencies of either FIX or FXI on the survival of mice expressing low levels of TF. Low-TF;FIX-/y male mice were born at the expected frequency, but none survived to wean. In contrast, low-TF;FXI-/- mice were generated at the expected frequency at wean and had a 6-month survival equivalent to that of low-TF mice. Surprisingly, a deficiency of FXI, but not FIX, exacerbated the size of blood pools in low-TF placentas and led to acute hemorrhage and death of some pregnant dams. Our data indicate that FIX, but not FXI, is essential for survival of low-TF mice after birth. This finding suggests that TF-FVIIa-mediated activation of FIX plays a critical role in murine hemostasis. In contrast, FXI deficiency, but not FIX deficiency, exacerbated blood pooling in low-TF placentas, indicating a tissue-specific requirement for FXI in the murine placenta under conditions of low TF.