Molecular analysis of human endometrium: short-term tibolone signaling differs significantly from estrogen and estrogen + progestagen signaling

Hanifi-Moghaddam, Payman; Boers-Sijmons, B.; Klaassens, Anet H.A.; Wijk, F. H. van; Bakker, Michael A. den; Ott, M.; Shipley, Gregory L.; Verheul, H.A.M.; Kloosterboer, Helenius J.; Burger, Curt W.; Blok, Leen J.

doi:10.1007/s00109-006-0146-1

Cited by 18 publications

(32 citation statements)

References 29 publications

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“…A description of the inclusion and exclusion criteria and of the histologic and molecular findings in the endometrium was documented earlier (1,24). The study groups were control group (8 subjects, no hormonal treatment), E 2 group (7 subjects, 2 mg of E 2 administered orally everyday, starting 21 d before surgery), and E 2 + MPA group (6 subjects, 2 mg E 2 + 5 mg MPA administered orally everyday, starting 21 d before surgery).…”

Section: Methodsmentioning

confidence: 99%

“…Raw data of both studies (24,25) were normalized as a group using robust multiarray analysis normalization (26). From the Talbi data (25), we only used gene expression data from well-characterized tissue samples (Table 1 from ref.…”

Section: Translational Relevancementioning

confidence: 99%

“…Genes with differential expression due to difference in tissue source, rather than hormonal effects, were identified and excluded from subsequent analysis. Cluster analysis was done as described by Hanifi-Moghaddam et al (24). Pathway analyses were conducted using Ingenuity Pathway software.…”

Section: Translational Relevancementioning

confidence: 99%

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Progesterone Inhibition of Wnt/β-Catenin Signaling in Normal Endometrium and Endometrial Cancer

Wang

Hanifi-Moghaddam

Hanekamp

et al. 2009

Clinical Cancer Research

120

114

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Purpose. Wnt signaling regulates the fine balance between stemness and differentiation. Here, the role of Wnt signaling to maintain the balance between estrogen-induced proliferation and progesterone-induced differentiation during the menstrual cycle, as well as during the induction of hyperplasia and carcinogenesis of the endometrium, was investigated. Experimental Design: Endometrial gene expression profiles from estradiol (E 2 ) and E 2 + medroxyprogesterone acetate-treated postmenopausal patients were combined with profiles obtained during the menstrual cycle (PubMed; GEO DataSets). Ishikawa cells were transfected with progesterone receptors and Wnt inhibitors dickkopf homologue 1 (DKK1) and forkhead box O1 (FOXO1), measuring Wnt activation. Expression of DKK1 and FOXO1 was inhibited by use of sequence-specific short hairpins. Furthermore, patient samples (hormone-treated endometria, hyperplasia, and endometrial cancer) were stained for Wnt activation using nuclear β-catenin and CD44. Results: In vivo, targets and components of the Wnt signaling pathway (among them DKK1 and FOXO1) are regulated by E 2 and progesterone. In Wnt-activated Ishikawa cells, progesterone inhibits Wnt signaling by induction of DKK1 and FOXO1. Furthermore, using siRNA-mediated knockdown of both DKK1 and FOXO1, progesterone inhibition of Wnt signaling was partly circumvented. Subsequently, immunohistochemical analysis of the Wnt target gene CD44 showed that progesterone acted as an inhibitor of Wnt signaling in hyperplasia and in well-differentiated endometrial cancer. The female sex hormones estradiol (E 2 ) and progesterone play rate-limiting roles in the cyclical renewal of the inner layer of the uterus (endometrium). In the first half of the regular menstrual cycle, the proliferation phase, E 2 is required to expand the endometrial layer by inducing cell proliferation. In the second half of the menstrual cycle, the secretory phase, progesterone levels increase, which antagonizes the proliferative activity of E 2 by inducing differentiation of epithelial and stromal cells of the endometrium (1). Thus, inhibition of E 2 -induced proliferation by progesterone is crucial for the maintenance of homeostasis in the endometrium.Increased estrogen signaling often underlies endometrial hyperplasia and is a well-established risk factor for endometrial cancer (2). Because progesterone inhibits estrogen-induced endometrial proliferation, progesterone has been used in its synthetic form [i.e., medroxyprogesterone acetate (MPA)] in palliative treatment of advanced and recurrent endometrial cancer with modest though significant response rates (15-25%; ref. 3). Progesterone has also been used as a primary treatment for endometrial carcinoma confined to the endometrial layer of the uterus, for example, in premenopausal women determined to preserve fertility. Response rates in these women can be up to 60% (4, 5), indicating that progesterone signaling in well-differentiated endometrial cancer is a potent inhibitor of endometrial carcinogene...

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Section: Methodsmentioning

confidence: 99%

Section: Translational Relevancementioning

confidence: 99%

See 1 more Smart Citation

Progesterone Inhibition of Wnt/β-Catenin Signaling in Normal Endometrium and Endometrial Cancer

Wang

Hanifi-Moghaddam

Hanekamp

et al. 2009

Clinical Cancer Research

120

114

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“…Handling of tissues was done in such a way to minimize variation induced by technical handling. 14 The study design was approved by the Medical Ethical Committee and all women gave written informed consent.…”

Section: Patient Samplesmentioning

confidence: 99%

HPV related VIN: Highly proliferative and diminished responsiveness to extracellular signals

Santegoets

Seters

Helmerhorst

et al. 2007

Intl Journal of Cancer

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Vulvar intraepithelial neoplasia (VIN) is a premalignant disorder caused by human papillomaviruses. Basic knowledge about the molecular pathogenesis of VIN is sparse. Therefore, we have analyzed the gene expression profile of 9 VIN samples in comparison to 10 control samples by using genome wide Affymetrix Human U133A plus2 GeneChips. Results were validated by quantitative real-time RT-PCR analysis and immunostaining of a few representative genes (TACSTD1, CCNE2, AR and ESR1). Significance analysis of microarrays (SAM) showed that 1,497 genes were differentially expressed in VIN compared to controls. By analyzing the biological processes affected by the observed differences, we found that VIN appears to be a highly proliferative disease; many cyclins (CCNA, CCNB and CCNE) and almost all prereplication complex proteins are upregulated. Thereby, VIN does not seem to depend for its proliferation on paracrine or endocrine signals. Many receptors (for example ESR1 and AR) and ligands are downregulated. Furthermore, although VIN is not an invasive disease, the inhibition of expression of a marked number of cell-cell adhesion molecules seems to indicate development towards invasion. Upon reviewing apoptosis and angiogenesis, it was observed that these processes have not become significantly disregulated in VIN. In conclusion: although VIN is still a premalignant disease, it already displays several hallmarks of cancer. 1 Differentiated type VIN is mostly found in postmenopausal women and is associated with lichen sclerosus. In contrast, Usual type VIN (undifferentiated) is often diagnosed in premenopausal women and is strongly associated with sexually transmitted Human papilloma virus (HPV) infections. In this report, we will focus on HPVrelated, Usual Type VIN.During the last decade, VIN has been diagnosed with increasing frequency in relatively young women in western countries. This rise in incidence could be the result of a higher awareness and knowledge of VIN, but is more likely to be due to the overall increase in sexually transmitted diseases, and especially the rise in HPV infections. Around 40% of young, sexually active women are infected with high-risk HPV. 2 Fortunately most women are able to clear the infection, and less than 10% of infected women develop a persistent HPV infection which causes dysplasia of the lower genital tract and might cause VIN.3 Such a persistent infection with high-risk HPV (mostly HPV16, 18, 31 or 33) may trigger VIN to further develop into invasive vulvar cancer. What percentage of women with VIN eventually develop cancer is difficult to assess, because most patients with VIN will be treated effectively.van Seters et al. have reviewed data on 3,322 published patients with VIN and found 88 untreated patients, of whom 8 (9%) progressed to vulvar cancer. 4 A critical step in the defence against high-risk HPV is a good immune response. Accordingly, being immunocompromised is a risk factor for the development of VIN and subsequent vulvar cancer. For example, VIN is observed more often ...

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“…In addition to the data sets described above, we analyzed a data set coming from the comparison of expression levels at days 7 and 0 in the fat remodeling experiment, a data set investigating the effect of various types of hormones on the endometrium of healthy post-menopausal women who underwent hysterectomy (Hanifi-Moghaddam et al 2007), as well as a data set requested by one of the reviewers, investigating the correlation between gene expression values ''with MiniMental Status Examination ( MMSE) and neurofibrillary tangle (NFT)'' in subjects with Alzheimer's disease (Blalock et al 2004). The latter data set was analyzed to identify significant pathways from both KEGG and Reactome databases (see the Supplemental Results section in the Supplemental Material).…”

Section: Detection Analysis and Correction Of Crosstalkmentioning

confidence: 99%

Analysis and correction of crosstalk effects in pathway analysis

et al. 2013

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Identifying the pathways that are significantly impacted in a given condition is a crucial step in understanding the underlying biological phenomena. All approaches currently available for this purpose calculate a P-value that aims to quantify the significance of the involvement of each pathway in the given phenotype. These P-values were previously thought to be independent. Here we show that this is not the case, and that many pathways can considerably affect each other's P-values through a ''crosstalk'' phenomenon. Although it is intuitive that various pathways could influence each other, the presence and extent of this phenomenon have not been rigorously studied and, most importantly, there is no currently available technique able to quantify the amount of such crosstalk. Here, we show that all three major categories of pathway analysis methods (enrichment analysis, functional class scoring, and topology-based methods) are severely influenced by crosstalk phenomena. Using real pathways and data, we show that in some cases pathways with significant P-values are not biologically meaningful, and that some biologically meaningful pathways with nonsignificant P-values become statistically significant when the crosstalk effects of other pathways are removed. We describe a technique able to detect, quantify, and correct crosstalk effects, as well as identify independent functional modules. We assessed this novel approach on data from four experiments involving three phenotypes and two species. This method is expected to allow a better understanding of individual experiment results, as well as a more refined definition of the existing signaling pathways for specific phenotypes.

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Molecular analysis of human endometrium: short-term tibolone signaling differs significantly from estrogen and estrogen + progestagen signaling

Cited by 18 publications

References 29 publications

Progesterone Inhibition of Wnt/β-Catenin Signaling in Normal Endometrium and Endometrial Cancer

Progesterone Inhibition of Wnt/β-Catenin Signaling in Normal Endometrium and Endometrial Cancer

HPV related VIN: Highly proliferative and diminished responsiveness to extracellular signals

Analysis and correction of crosstalk effects in pathway analysis

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