{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T08:33:19Z","timestamp":1791275599241,"version":"4.1.0"},"reference-count":48,"publisher":"National Academy of Sciences","issue":"33","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2010,8,17]]},"abstract":"<jats:p>\n                    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\u2013\u03b2 (LXR\u03b2) has been inactivated, preneoplastic lesions of the gallbladder developed and evolved to cancer in old animals. LXR\u03b2 is a nuclear receptor involved in the control of lipid homeostasis, glucose metabolism, inflammation, proliferation, and CNS development. LXR\u03b2\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    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 LXR\u03b1\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    or LXR\u03b1\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    \u03b2\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    animals of either sex. Interestingly, the elimination of estrogens with ovariectomy prevented development of preneoplastic lesions in LXR\u03b2\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice. The etiopathological mechanism seems to involve TGF-\u03b2 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 LXR\u03b2 in a complex interplay with estrogens and TGF-\u03b2 could play a crucial role in the malignant transformation of the gallbladder epithelium.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1009483107","type":"journal-article","created":{"date-parts":[[2010,8,2]],"date-time":"2010-08-02T23:35:49Z","timestamp":1280792149000},"page":"14763-14768","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":60,"title":["Estrogen-dependent gallbladder carcinogenesis in LXR\u03b2\n                    <sup>\u2212\/\u2212<\/sup>\n                    female mice"],"prefix":"10.1073","volume":"107","author":[{"given":"Chiara","family":"Gabbi","sequence":"first","affiliation":[{"name":"Department of Biosciences and Nutrition, Karolinska Institutet, S-141 86 Novum, Sweden; and"},{"name":"Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX 77204"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyun-Jin","family":"Kim","sequence":"additional","affiliation":[{"name":"Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX 77204"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodrigo","family":"Barros","sequence":"additional","affiliation":[{"name":"Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX 77204"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marion","family":"Korach-Andr\u00e8","sequence":"additional","affiliation":[{"name":"Department of Biosciences and Nutrition, Karolinska Institutet, S-141 86 Novum, Sweden; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret","family":"Warner","sequence":"additional","affiliation":[{"name":"Department of Biosciences and Nutrition, Karolinska Institutet, S-141 86 Novum, Sweden; and"},{"name":"Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX 77204"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan-\u00c5ke","family":"Gustafsson","sequence":"additional","affiliation":[{"name":"Department of Biosciences and Nutrition, Karolinska Institutet, S-141 86 Novum, Sweden; and"},{"name":"Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX 77204"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2010,8,2]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1128\/mcb.14.10.7025-7035.1994"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.6.2096"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.11.3.289"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.1.266"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81432-4"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M411080200"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.844900"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111041200"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M210208200"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.23436"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-06-0632"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/bgp029"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1210\/en.2006-1247"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-008-1174-x"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.1008663"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0811295106"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1210\/me.2007-0187"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.3322\/canjclin.48.1.6"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.3322\/canjclin.51.6.349"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(03)01021-0"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1002\/1097-0142(19920915)70:6<1493::AID-CNCR2820700608>3.0.CO;2-U"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/18.1.50"},{"key":"e_1_3_3_23_2","first-page":"CD004143","article-title":"Long term hormone therapy for perimenopausal and postmenopausal women","author":"Farquhar C","year":"2009","unstructured":"C Farquhar, J Marjoribanks, A Lethaby, JA Suckling, Q Lamberts, Long term hormone therapy for perimenopausal and postmenopausal women. 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