| First Author | Gabbi C | Year | 2010 |
| Journal | Proc Natl Acad Sci U S A | Volume | 107 |
| Issue | 33 | Pages | 14763-8 |
| PubMed ID | 20679224 | Mgi Jnum | J:163706 |
| Mgi Id | MGI:4829562 | Doi | 10.1073/pnas.1009483107 |
| Citation | Gabbi C, et al. (2010) Estrogen-dependent gallbladder carcinogenesis in LXRbeta-/- female mice. Proc Natl Acad Sci U S A 107(33):14763-8 |
| abstractText | Gallbladder cancer is a highly aggressive disease with poor prognosis that is two to six times more frequent in women than men. The development of gallbladder cancer occurs over a long time (more than 15 y) and evolves from chronic inflammation to dysplasia/metaplasia, carcinoma in situ, and invasive carcinoma. In the present study we found that, in female mice in which the oxysterol receptor liver X receptor-beta (LXRbeta) has been inactivated, preneoplastic lesions of the gallbladder developed and evolved to cancer in old animals. LXRbeta is a nuclear receptor involved in the control of lipid homeostasis, glucose metabolism, inflammation, proliferation, and CNS development. LXRbeta(-/-) female gallbladders were severely inflamed, with regions of dysplasia and high cell density, hyperchromasia, metaplasia, and adenomas. No abnormalities were evident in male mice, nor in LXRalpha(-/-) or LXRalpha(-/-)beta(-/-) animals of either sex. Interestingly, the elimination of estrogens with ovariectomy prevented development of preneoplastic lesions in LXRbeta(-/-) mice. The etiopathological mechanism seems to involve TGF-beta signaling, as the precancerous lesions were characterized by strong nuclear reactivity of phospho-SMAD-2 and SMAD-4 and loss of E-cadherin expression. Upon ovariectomy, E-cadherin was reexpressed on the cell membranes and immunoreactivity of pSMAD-2 in the nuclei was reduced. These findings suggest that LXRbeta in a complex interplay with estrogens and TGF-beta could play a crucial role in the malignant transformation of the gallbladder epithelium. |
