Expression of Estrogen Receptor β in Colon Cancer Progression

Leung

Journal of Endocrinology

et al. 2014

Ovarian cancer cells express both estrogen receptor a (ERa) and ERb, and hormonal therapy is an attractive treatment option because of its relatively few side effects. However, estrogen was previously shown to have opposite effects in tumors expressing ERa compared with ERb, indicating that the two receptor subtypes may have opposing effects. This may explain the modest response to nonselective estrogen inhibition in clinical practice. In this study, we aimed to investigate the effect of selectively targeting each ER subtype on ovarian cancer growth. Ovarian cancer cell lines SKOV3 and OV2008, expressing both ER subtypes, were treated with highly selective ER modulators. These results were confirmed on a xenograft model where SKOV3 cells were injected s.c. into ovariectomized mice. We observed that the average size of xenografts in both the DPN-treated group and the MPP-treated group was significantly smaller than that for the vehicle-treated group. In addition, we found that phospho-AKT expressions in SKOV3 cells were reduced by 80% after treatment with MPP and DPN, indicating that the AKT pathway was involved. The combined treatment with MPP and DPN had a synergistic effect in suppressing ovarian cancer cell growth. Our findings indicate that targeting ER subtypes may enhance the response to hormonal treatment in women with ovarian cancer.

Section: Discussionmentioning

confidence: 99%

Targeting estrogen receptor subtypes (ERα and ERβ) with selective ER modulators in ovarian cancer

Leung

Journal of Endocrinology

et al. 2014

Endocrine-Related Cancer

“…Other groups have shown that ERbKO mice are more susceptible to inflammation-associated colon cancer than the WT mice (Saleiro et al 2012). Clinical and experimental models of colonic carcinogenesis have suggested that the protein expression of ERb decreases as the tissues progress from a normal colonic epithelial to a malignant state (Konstantinopoulos et al 2003, Castiglione et al 2008, Di Leo et al 2008, Mostafaie et al 2009). In fact, humans with colon tumors not expressing ERb are likely to be in more advanced stages of cancer and have a higher risk for death compared with those with tumors in which ERb is present (Rudolph et al 2012).…”

Section: Discussionmentioning

confidence: 99%

A novel shift in estrogen receptor expression occurs as estradiol suppresses inflammation-associated colon tumor formation

Armstrong¹,

Billimek²,

Allred³

et al. 2013

Postmenopausal women on estrogen replacement therapy (ERT) have a reduced risk of developing colon cancer compared with postmenopausal women not on ERT, suggesting a role for estradiol (E 2 ) in protection against this disease. To determine whether E 2 protects against inflammation-associated colon cancer when administered following the initiation of colonic DNA damage, in this study, we implanted E 2 -containing pellets into mice after co-treatment with azoxymethane and two rounds of dextran sulfate sodium (DSS). Wild-type (WT) E 2 -treated mice had reduced numbers and average area of adenocarcinomas compared with the control mice. These effects were lost in estrogen receptor-b (Erb (Esr2)) knockout mice. Surprisingly, apoptosis was reduced and cell proliferation was increased in sections from tumors of the WT E 2 mice compared with the WT control mice. These findings are probably due, in part, to a reduction in ERb expression in colonic epithelial cells as the cells progressed from a non-malignant to a cancerous state as enhanced apoptosis was observed in normal colonocytes expressing higher levels of ERb. Furthermore, epithelial cells within the tumors had dramatically increased ERa mRNA and protein expression compared with the non-diseased mice. We conclude that while E 2 treatment resulted in an overall suppression of colonic adenocarcinoma formation, reduced ERb expression accompanied by enhanced ERa expression caused an altered colonocyte response to E 2 treatment compared with the earlier stages of colon cancer development. These data are the first examples of decreased ERb expression concurrent with increased ERa expression as a disease develops and highlight the importance of understanding the timing of E 2 exposure with regard to the prevention of inflammation-associated colon cancer.

“…It has been consistently reported that men have slightly higher rates of bile duct cancer than women (1); reasons for this are unclear but may be due to differences in prevalence of smoking, infection, occupational exposure or hormone-related factors between men and women (1,6). While ESRs have been more studied in women, they have also been linked to certain diseases in men, including cancers of the prostate and colon (31)(32)(33). In addition, in a study of ESR polymorphisms and plasma lipid levels, ESR1 variants, rs9322331 and rs9340799, were more strongly associated with apolipoprotein C in men but were more strongly associated with triglycerides in women, suggesting that ESR1 variation has sex-dependent effects on circulating lipid levels (33).…”

Section: Discussionmentioning

confidence: 99%

Polymorphisms of estrogen receptors and risk of biliary tract cancers and gallstones: a population-based study in Shanghai, China

et al. 2010

Biliary tract cancer encompasses tumors of the gallbladder, bile duct and ampulla of Vater. Gallbladder cancer is more common in women, whereas bile duct cancer is more common in men, suggesting that sex hormones may play a role in the etiology of these cancers. The intracellular action of estrogens is regulated by the estrogen receptor (ESR); thus, we examined the role of common genetic variants in ESR genes on the risk of biliary tract cancers and stones in a population-based case-control study in Shanghai, China (411 cancer cases, 895 stone cases and 786 controls). We genotyped six single-nucleotide polymorphisms (SNPs), four in ESR1 (rs2234693, rs3841686, rs2228480 and rs1801132) and two in ESR2 (rs1256049 and rs4986938). In all participants, the ESR1 rs1801132 (P325P) G allele was associated with excess risks of bile duct [odds ratio (OR) 5 1.7, 95% confidence interval (CI) 1.1-2.8] and ampulla of Vater cancers (OR 5 2.1, 95% CI 0.9-4.9) compared with the CC genotype. The association with bile duct cancer was apparent among men (OR 5 2.8, 95% CI 1.4-5.7) but not among women (P-heterogeneity 5 0.01). Also, the ESR2 rs4986938 (38 bp 3# of STP) GG genotype was associated with a higher risk of bile duct cancer (OR 5 3.3, 95% CI 1.3-8.7) compared with the AA genotype, although this estimate was based on a small number of subjects. None of the other SNPs examined was associated with biliary tract cancers or stones. False discovery rate-adjusted P-values were not significant (P > 0.1). No association was found for ESR1 haplotype based on four SNPs. These preliminary results suggest that variants in ESR genes could play a role in the etiology of biliary tract cancers, especially bile duct cancer in men.