Estrogen-dependent gallbladder carcinogenesis in LXRβ ^−/− female mice

Abstract

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-β (LXRβ) has been inactivated, preneoplastic lesions of the gallbladder developed and evolved to cancer in old animals. LXRβ is a nuclear receptor involved in the control of lipid homeostasis, glucose metabolism, inflammation, proliferation, and CNS development. LXRβ −/− 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 LXRα −/− or LXRαanimals of either sex. Interestingly, the elimination of estrogens with ovariectomy prevented development of preneoplastic lesions in LXRβ −/− mice. The etiopathological mechanism seems to involve TGF-β 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 LXRβ in a complex interplay with estrogens and TGF-β could play a crucial role in the malignant transformation of the gallbladder epithelium.cancer | hormone | oxysterols | SMAD | E-cadherin

Potential Therapeutic Targets for the Primary Gallbladder Carcinoma: Estrogen Receptors

“…Therefore, exploring new treatment targets for GBC is an urgent matter at present. Epidemiological studies displayed that incidence of GBC exhibited distinct gender biasness, which affected females two to three times than males (Lazcano-Ponce et al, 2001;Gabbi et al, 2010). This gender predominance indicated that estrogen may be a possible promoter of carcinogenesis in gallbladder.…”

Body Mass Index and the Risk of Gallbladder Cancer: An Updated Meta-analysis of Epidemiologic Studies

“…In addition, female sex hormones adversely influence hepatic bile secretion and gallbladder function [39]. Estrogens increase cholesterol secretion and diminish bile salt secretion, while progestins act by reducing bile salt secretion and impairing gallbladder emptying leading to stasis [40]. These may partially explain the stronger association observed with overweight or obesity in women than in men.…”

Carcinosarcoma of Gallbladder with Metastases in Liver and a Lymph Node

“…Most of the cases of this tumor are females. In addition, ovariectomized estrogen-free LXRβ -/-mice failed to develop preneoplastic lesions 3 . These observations suggest role of estrogen in gallbladder carcinogenesis.…”