Oestrogens promote tumorigenesis in a mouse model for colitis-associated cancer

Heijmans, Jarom; Wielenga, Mattheus C.B.; Rosekrans, Sanne; Jeude, Jooske F. van Lidth de; Roelofs, Joris J. T. H.; Groothuis, Patrick G.; Ederveen, A. G. H.; Jonge‐Muller, Eveline S. M. de; Biemond, I.; Hardwick, James C.H.; D’Haens, Geert R.; Hommes, Daniël W.; Muncan, Vanesa; Brink, Gijs R. van den

doi:10.1136/gutjnl-2012-304216

Cited by 37 publications

(32 citation statements)

References 27 publications

(30 reference statements)

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“…One report described a significant reduction in colonic adenomas after OVX, with a reversal to normal numbers by supplementation with 17β-estradiol (22). This tumor-promoting role for estrogens is consistent with the strong estrogen enhancement effect on colonic tumorigenesis associated with inflammation in the mouse (23). This estrogen effect was not reproduced in a subsequent report by the same group, however (24).…”

Section: Discussionsupporting

confidence: 72%

Sex disparity in colonic adenomagenesis involves promotion by male hormones, not protection by female hormones

Amos‐Landgraf

Heijmans

Wielenga

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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It recently has been recognized that men develop colonic adenomas and carcinomas at an earlier age and at a higher rate than women. In the Apc Pirc/+ (Pirc) rat model of early colonic cancer, this sex susceptibility was recapitulated, with male Pirc rats developing twice as many adenomas as females. Analysis of large datasets revealed that the Apc Min/+ mouse also shows enhanced male susceptibility to adenomagenesis, but only in the colon. In addition, WT mice treated with injections of the carcinogen azoxymethane (AOM) showed increased numbers of colonic adenomas in males. The mechanism underlying these observations was investigated by manipulation of hormonal status. The preponderance of colonic adenomas in the Pirc rat model allowed a statistically significant investigation in vivo of the mechanism of sex hormone action on the development of colonic adenomas. Females depleted of endogenous hormones by ovariectomy did not exhibit a change in prevalence of adenomas, nor was any effect observed with replacement of one or a combination of female hormones. In contrast, depletion of male hormones by orchidectomy (castration) markedly protected the Pirc rat from adenoma development, whereas supplementation with testosterone reversed that effect. These observations were recapitulated in the AOM mouse model. Androgen receptor was undetectable in the colon or adenomas, making it likely that testosterone acts indirectly on the tumor lineage. Our findings suggest that indirect tumor-promoting effects of testosterone likely explain the disparity between the sexes in the development of colonic adenomas.colon cancer | animal models | androgens | estrogens | intestinal regionality E pidemiologic studies have identified a number of factors that influence the risk of sporadic adenomas and colorectal cancer (CRC). Age, familial predisposition, racial background, diet, physical activity, obesity and the metabolic syndrome, smoking, and heavy alcohol use are all established risk factors for the development of CRC. In addition, the risk of CRC also shows sexual dimorphism, with a lower incidence and delayed onset in women (1, 2). Colonoscopic screening of asymptomatic individuals has corroborated male sex as a risk factor for the development of both adenomas and CRC in all age groups (3, 4); however, whether this disparity depends on protective factors in women, tumor-promoting factors in males, or both is unknown.A protective role of female hormones against the development of frank CRC is suggested by data from the Women's Health Initiative (WHI). In the WHI, two large randomized controlled trials examined the effects of hormonal replacement therapy on postmenopausal women over a 5-y period, using CRC development as one of the endpoints. The first study showed that combined treatment with both equine estrogen (E2) and medroxyprogesterone acetate (MPA) substantially reduced the risk of colorectal cancer compared with placebo (odds ratio, 0.63) after a 5-y follow-up (5). However, protection was not found in a second randomized cont...

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Section: Discussionsupporting

confidence: 72%

Sex disparity in colonic adenomagenesis involves promotion by male hormones, not protection by female hormones

Amos‐Landgraf

Heijmans

Wielenga

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

111

101

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“…Consistent with this, colonic paracellular permeability decreases during the oestrus phase (high levels of estrogen) of the rat when compared to the dioestrus phase (low levels of estrogen) [89]. Although estrogen treatment has been shown to predispose ovariectomized rats to development of ulcerative colitis-induced tumor development [90], most studies to-date have shown that estrogen treatment decreases colonic paracellular permeability and reduces IBD symptom severity [89, 91, 92]. ERβ is the predominant estrogen receptor in the intestinal tract.…”

Section: Barrier Pathophysiology In Developmentmentioning

confidence: 91%

Epithelial Barrier Function in Gut-Bone Signaling

Rios‐Arce

Collins

Schepper

et al. 2017

Advances in Experimental Medicine and Biology

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The intestinal epithelial barrier plays an essential role in maintaining host homeostasis. The barrier regulates nutrient absorption as well as prevents the invasion of pathogenic bacteria in the host. It is composed of epithelial cells, tight junctions, and a mucus layer. Several factors, such as cytokines, diet, and diseases can affect this barrier. These factors have been shown to increase intestinal permeability, inflammation, and translocation of pathogenic bacteria. In addition, dysregulation of the epithelial barrier can result in inflammatory diseases such as inflammatory bowel disease. Our lab and others have also shown that barrier disruption can have systemic effects including bone loss. In this chapter, we will discuss the current literature to understand the link between intestinal barrier and bone. We will discuss how inflammation, aging, dysbiosis and metabolic diseases can affect intestinal barrier-bone link. In addition, we will highlight the current suggested mechanism between intestinal barrier and bone.

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“…20,21 Although the impact that p53 has on AOM-induced CRC remains unclear, AOM has a documented relationship with estrogen signaling pathways, and specifically with estrogen receptor alpha (ERα). Estrogen has been demonstrated to promote tumorigenesis in AOM mouse models 22 and other studies have shown a dramatic increase in ERα expression in tumorous tissue after AOM treatment. 23 In this study, we used AOM to induce sporadic colon cancer in genetically engineered mice harboring either the Mdm2 SNP309-G or Mdm2 SNP309-T allele.…”

Section: Introductionmentioning

confidence: 94%

Impact of the Mdm2SNP309-G allele on a murine model of colorectal cancer

2014

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A single-nucleotide polymorphism (SNP) in the promoter of the Mdm2 gene (Mdm2(SNP309-G)) results in an increased Mdm2 expression, partial attenuation of the p53 pathway and accelerated tumor development. Clinical case-control studies indicate the Mdm2(SNP309-)(G) allele associates with a significant increase in colorectal cancer (CRC) risk that is heightened in women, but the biological significance of this polymorphism has never been directly evaluated. To examine whether the Mdm2(SNP309-)(G) allele contributes to colorectal cancer, we generated cohorts of mice harboring either the G (minor allelic variant) or T (major allelic variant) allele and treated them with azoxymethane (AOM), a carcinogen that induces sporadic colorectal cancer. Mdm2(SNP309-G/G) mice displayed a significant reduction in survival following AOM treatment with more colonic lesions in a wider distribution throughout the lower and upper colon and an attenuated apoptotic response following exposure. AOM did not significantly induce stabilization of wild-type p53 or activate p53 downstream targets following AOM treatment, regardless of the genotype. Instead, Mdm2(SNP309-G/G) colons had significant changes in the expression of genes that regulate Mdm2 transcription (ERα and Sp1) as well as downstream targets of Mdm2. Together these results suggest the Mdm2(SNP309-)(G) allele significantly impacts CRC through mechanisms outside the p53 pathway.

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Oestrogens promote tumorigenesis in a mouse model for colitis-associated cancer

Abstract: Our results suggest that oestrogens promote inflammation-associated cancer development by impairing the mucosal response to inflammatory damage.

Cited by 37 publications

References 27 publications

Sex disparity in colonic adenomagenesis involves promotion by male hormones, not protection by female hormones

Sex disparity in colonic adenomagenesis involves promotion by male hormones, not protection by female hormones

Epithelial Barrier Function in Gut-Bone Signaling

Impact of the Mdm2SNP309-G allele on a murine model of colorectal cancer

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