Figure 3.
Mice with reduced γ-secretase activity develop spontaneous tumors. A, Protein extracts (40 μg each) from skin of Nct+/+ and Nct+/− mice were immunoblotted with antisera specific to Nct, PS1–NTF, PS1–CTF, or PEN-2. Immunoblots were striped and reprobed using antiserum against β-tubulin as loading control. B, Protein extracts (40 μg each) from skins of Nct+/− and Nct+/−;PS1+/− mice were immunoblotted with antisera specific to Nct, PS1–NTF, PS1–CTF, or PEN-2. Immunoblots were striped and reprobed using antiserum against actin as loading control. C, Kaplan–Meyer plots of tumor development in Nct+/+, Nct+/−, and Nct+/−;PS1+/− mice. Kaplan–Meyer plots of tumor development in Nct+/+ (n = 96) and Nct+/− (n = 89) mice. Note that Nct+/− mice developed tumors with median age of ∼60 weeks, and >90% of Nct+/− mice developed skin tumors by 100 weeks of age; none of Nct+/+ mice developed skin tumors by this age. The median age of tumor development in Nct+/−;PS1+/− mice is greatly accelerated when compared with Nct+/− mice (45 vs 60 weeks), and >90% of Nct+/−;PS1+/− mice developed skin tumors by 60 weeks of age (p < 0.0001). D, Kaplan–Meyer survival plots for Nct+/+, Nct+/−, and Nct+/−;PS1+/− mice. Compared with wild-type mice, Nct+/− mice have a significantly shorter lifespan, with a median life expectancy of 94 weeks, whereas Nct+/−;PS1+/− mice have a further shortened lifespan, with median life expectancy of 71 weeks (p < 0.0001). Death is defined as the time when mice became moribund. E, SCC near the tail of Nct+/− mice (33 weeks of age) shows moderately well differentiated invasive clusters of squamous type epithelial cells (4×). F, Higher magnification (20×) of E (boxed area) showing moderately well differentiated invasive clusters of squamous type epithelial cells with cornification, disorganization, atypia, and mitotic figures (arrowheads). G, Squamous cell carcinoma (arrows) metastasized to the renal cortex in an Nct+/− mouse (98 weeks of age) (4×). H, Higher magnification (40×) of skin lesions in Nct+/−;PS1+/− mice (21 weeks of ages) showing clusters of squamous epithelial cells with disorganization, atypia, and mitotic figures (arrowheads). All sections (10 μm) were stained with hematoxylin and eosin.