Conditional Inactivation of Brca1, p53 and Rb in Mouse Ovaries Results in the Development of Leiomyosarcomas

Epithelial ovarian cancer (EOC) is thought to arise in part from the ovarian surface epithelium (OSE); however, the molecular events underlying this transformation are poorly understood. Germline mutations in the BRCA1 tumor suppressor gene result in a significantly increased risk of developing EOC and a large proportion of sporadic EOCs display some sort of BRCA1 dysfunction. To generate a model in which Brca1-mediated transformation can be studied, we previously inactivated Brca1 alone in murine OSE, which resulted in an increased accumulation of premalignant changes, but no tumor formation. In this study, we examined tumor formation in mice with conditionally expressed alleles of Brca1, p53 and Rb, alone or in combination. Intrabursal injection of adenovirus expressing Cre recombinase to inactivate p53 resulted in tumors in 100% of mice. Tumor progression was accelerated in mice with concomitant inactivation of Brca1 and p53, but not Rb and p53. Immunohistologic analyses classified the tumors as leiomyosarcomas that may be arising from the ovarian bursa. Brca1 inactivation in primary cultures of murine OSE cells led to a suppression of proliferation that could be rescued by concomitant inactivation of p53 and/or Rb. Brca1-deficient OSE cells displayed an increased sensitivity to the DNA damaging agent cisplatin, and this effect could be modulated by inactivation of p53 and/or Rb. These results indicate that Brca1 deficiency can accelerate tumor development and alter the sensitivity of OSE cells to chemotherapeutic agents. Intrabursal delivery of adenovirus intended to alter gene expression in the ovarian surface epithelium may, in some strains of mice, result in more rapid transformation of adjacent cells, resulting in leiomyosarcomas

Preeclampsia is a biomarker for vascular disease in both mother and child: the need for a medical alert system

This paper reviews the literature pertaining to the impact of preeclampsia not only on the mother but particularly on the children. The review points to the higher blood pressure in children born to preeclamptic mothers compared to controls, their increased tendency to suffer strokes, the reduction in their cognitive ability, and their vulnerability to depression. Mechanisms that may induce these changes are emphasized, particularly the placental vascular insufficiency and the resulting hypoxic and proinflammatory environments in which the fetus develops. The hypothesis proposed is that these changes in the fetal-placental environment result in epigenetic programming of the child towards a higher propensity for vascular disease. The review's main recommendation is that, within ethical boundaries, the medical records of individuals born to preeclamptic mothers should clearly indicate this event and should be made available to the affected individuals so that preventive measures against vascular complications and lifestyle changes that may mitigate the latter can be instituted

Preeclampsia Is a Biomarker for Vascular Disease in Both Mother and Child: The Need for a Medical Alert System

This paper reviews the literature pertaining to the impact of preeclampsia not only on the mother but particularly on the children. The review points to the higher blood pressure in children born to preeclamptic mothers compared to controls, their increased tendency to suffer strokes, the reduction in their cognitive ability, and their vulnerability to depression. Mechanisms that may induce these changes are emphasized, particularly the placental vascular insufficiency and the resulting hypoxic and proinflammatory environments in which the fetus develops. The hypothesis proposed is that these changes in the fetal-placental environment result in epigenetic programming of the child towards a higher propensity for vascular disease. The review’s main recommendation is that, within ethical boundaries, the medical records of individuals born to preeclamptic mothers should clearly indicate this event and should be made available to the affected individuals so that preventive measures against vascular complications and lifestyle changes that may mitigate the latter can be instituted

Survival of mice following inactivation of multiple tumor suppressors in the OSE <i>in vivo</i>.

<p>Kaplan-Meier plots showing the time to loss-of-wellness endpoint of the mice in which <i>Brca1</i>, <i>p53</i>, and/or <i>Rb</i> had been inactivated in the OSE. <b>A</b>) The median survival time of the <i>Brca1</i>^Δ5-13/<i>p53</i>^Δ2-10 mice (147.5 days) is significantly shorter than that of the <i>p53</i>^Δ2-10 mice (179.5 days), P<0.05. <b>B</b>) The median survival time of the <i>Brca1</i>^Δ5-13/<i>p53</i>^Δ2-10 mice (147.5 days) is significantly less than that of the <i>Rb</i>^Δ19/<i>p53</i>^Δ2-10 mice (170 days), P<0.001. <b>C</b>) The median survival time of the <i>Rb</i>^Δ19/<i>p53</i>^Δ2-10/<i>Brca1</i>^Δ5-13 mice (118.5 days) is significantly less than that of the <i>Rb</i>^Δ19/<i>p53</i>^Δ2-10 mice (170 days), P<0.05. <b>D</b>) The median survival time of the <i>Rb</i>^Δ19/<i>p53</i>^Δ2-10/<i>Brca1</i>^Δ5-13 mice (118.5 days) is less than that of the <i>Brca1</i>^Δ5-13/<i>p53</i>^Δ2-10 mice (147.5 days), although the difference in survival was not statistically significant.</p

Tumor formation following intrabursal injection of adenoviral Cre recombinase.

a<p>Number of mice indicates the number of animals who received intrabursal injection of adenoviral Cre recombinase and were euthanized when they had reached a loss-of-wellness endpoint due to tumor burden or had reached the 240 day time point.</p

Pressure-Tuning Fourier Transform Infrared Spectroscopic Study of Carcinogenesis in Human Endometrium

NRC publication: Ye

Distribution of morphological features in the OSE over time following conditional inactivation of <i>Rb</i> and <i>Brca1</i>.

<p>Numbers represent the mean±SEM of the number of morphological changes per section over five non-consecutive sections in n ovaries. Letters are used to denote a significant difference between time points for that treatment group.</p

Representative images of tumor histology.

<p>Paraffin sections (5 µm) of the tumors were stained with H&E or specific antibodies to examine histology and gene expression: <b>A</b>) H&E (200X) <b>B</b>) cytokeratin19 (400X) <b>C</b>) smooth muscle actin (200X) <b>D</b>) desmin (100X) <b>E</b>) CD34 (100X). Antigen detection in B–E is by the presence of a brownish-red stain.</p