The synergistic effect of Mig-6 and Pten ablation on endometrial cancer development and progression.

Ablation of Mig-6 in the murine uterus leads to the development of endometrial hyperplasia and estrogen-induced endometrial cancer. An additional endometrial cancer mouse model is generated by the ablation of phosphatase and tensin homolog deleted from chromosome 10 (Pten) (either as heterozygotes or by conditional uterine ablation). To determine the interplay between Mig-6 and the PTEN/phosphoinositide 3-kinase signaling pathway during endometrial tumorigenesis, we generated mice with Mig-6 and Pten conditionally ablated in progesterone receptor-positive cells (PR(cre/+)Mig-6(f/f)Pten(f/f); Mig-6(d/d)Pten(d/d)). The ablation of both Mig-6 and Pten dramatically accelerated the development of endometrial cancer compared with the single ablation of either gene. The epithelium of Mig-6(d/d)Pten(d/d) mice showed a significant decrease in the number of apoptotic cells compared with Pten(d/d) mice. The expression of the estrogen-induced apoptotic inhibitors Birc1 was significantly increased in Mig-6(d/d)Pten(d/d) mice. We identified extracellular signal-regulated kinase 2 (ERK2) as an MIG-6 interacting protein by coimmunoprecipitation and demonstrated that the level of ERK2 phosphorylation was increased upon Mig-6 ablation either singly or in combination with Pten ablation. These results suggest that Mig-6 exerts a tumor-suppressor function in endometrial cancer by promoting epithelial cell apoptosis through the downregulation of the estrogen-induced apoptosis inhibitors Birc1 and the inhibition of ERK2 phosphorylation.

beta-catenin mediates glandular formation and dysregulation of beta-catenin induces hyperplasia formation in the murine uterus.

Endometrioid adenocarcinoma is the most frequent form of endometrial cancer, usually developing in pre- and peri-menopausal women. beta-catenin abnormalities are common in endometrioid type endometrial carcinomas with squamous differentiation. To investigate the role of beta-catenin (Ctnnb1) in uterine development and tumorigenesis, mice were generated which expressed a dominant stabilized beta-catenin or had beta-catenin conditionally ablated in the uterus by crossing the PR(Cre) mouse with the Ctnnb1(f(ex3)/+) mouse or Ctnnb1(f/f) mouse, respectively. Both of the beta-catenin mutant mice have fertility defects and the ability of the uterus to undergo a hormonally induced decidual reaction was lost. Expression of the dominant stabilized beta-catenin, PR(cre/+)Ctnnb1(f(ex3)/+), resulted in endometrial glandular hyperplasia, whereas ablation of beta-catenin, PR(cre/+)Ctnnb1(f/f), induced squamous cell metaplasia in the murine uterus. Therefore, we have demonstrated that correct regulation of beta-catenin is important for uterine function as well as in the regulation of endometrial epithelial differentiation.

Autoantibodies directed against sicca syndrome antigens in the neonatal lupus syndrome.

Clinical and serologic studies on three infants who had the neonatal lupus syndrome and studies on their mothers revealed an association with antibodies to sicca syndrome antigens. From initial studies and a 2-year follow-up, there is evidence that indicates transplacental passage of autoantibodies directed against Sjögren's (sicca) syndrome-associated nuclear antigens from asymptomatic mothers to newborns who subsequently developed neonatal lupus. Besides the presence of antinuclear antibodies, the mothers of these infants also showed high rheumatoid factor titers, and two had evidence of mild decreasing tearing on ophthalmologic examination. On follow-up examination 2 to 3 years later, both infants and mothers lacked evidence of active disease, and only the mothers continued to demonstrate the serologic abnormalities seen initially. Based on our findings, we postulate newborns of mothers with serologic or clinical evidence of Sjögren's (sicca) syndrome may be at greater risk for developing neonatal lupus.

Steroid rosacea in children.

Steroid rosacea is a facial dermatitis clinically resembling acne rosacea. Fluorinated topical steroids have been implicated as the cause or precipitating factor in previous case reports mainly involving an adult population. Four cases of pediatric acne rosacea associated with the use of topical fluorinated glucocorticosteroids are described. The process worsened during the two weeks following steroid cessation. We recommend that fluorinated glucocorticosteroids should not be used on the face of infants and children.