Association of Exogenous Estrogen and Endometrial Carcinoma

Smith, Donald C.; Prentice, Ross L.; Thompson, Donovan J.; Herrmann, Walter

doi:10.1097/00006254-197604000-00017

Cited by 96 publications

(124 citation statements)

References 0 publications

Supporting

Mentioning

115

Contrasting

Unclassified

Order By: Relevance

“…Chronic exposure to unopposed estrogen is a well-known risk factor for endometrial hyperplasia and cancer (19,20). In our model, increasing durations of exposure to high-dose estrogen unopposed by progesterone resulted in progressive endometrial pathology, demonstrated by increased gland to stromal ratio, and irregularly contoured glands with cytologic atypia (Fig.…”

Section: Dissociated Endometrial Glands Were Highly Enriched For Epitmentioning

confidence: 74%

Cell-autonomous activation of the PI3-kinase pathway initiates endometrial cancer from adult uterine epithelium

Memarzadeh¹,

Zong

Janzen³

et al. 2010

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

View full text Add to dashboard Cite

Epithelial-specific activation of the PI3-kinase pathway is the most common genetic alteration in type I endometrial cancer. In the majority of these tumors, PTEN expression is lost in the epithelium but maintained in tumor stroma. Currently reported PTEN knockout mouse models initiate type I endometrial cancer concomitant with loss of PTEN in both uterine epithelium and stroma. Consequently, the biologic outcome of selectively activating the PI3-kinase pathway in the endometrial epithelium remains unknown. To address this question, we established a malleable in vivo endometrial regeneration system from dissociated murine uterine epithelium and stroma. Regenerated endometrial glands responded to pharmacologic variations in hormonal milieu similar to the native endometrium. Cellautonomous activation of the PI3-kinase pathway via biallelic loss of PTEN or activation of AKT in adult uterine epithelia in this model was sufficient to initiate endometrial carcinoma. AKT-initiated tumors were serially transplantable, demonstrating permanent genetic changes in uterine epithelia. Immunohistochemistry confirmed loss of PTEN or activation of AKT in regenerated hyperplastic glands that were surrounded by wild-type stroma. We demonstrate that cell-autonomous activation of the PI3-kinase pathway is sufficient for the initiation of endometrial carcinoma in naive adult uterine epithelia. This in vivo model provides an ideal platform for testing the response of endometrial carcinoma to targeted therapy against this common genetic alteration.tissue regeneration model | progesterone receptor | uterine cancer E ndometrial cancer, the most common gynecologic cancer in the United States (1), is a hormonally regulated tumor arising from epithelial cells lining the uterine cavity. Effective targeted therapy is unavailable, partly because of lack of knowledge regarding basic biologic pathways and cellular compartments that can initiate this malignancy. Women diagnosed with endometrial cancer are treated in a similar manner irrespective of the heterogeneity of this disease, with surgery or combinations of radiation and chemotherapy. Although endometrial cancer can be cured in early stages, side effects associated with the current therapy can have lifelong debilitating effects on some patients. The majority of women diagnosed with late-stage or metastatic disease die, despite undergoing radical treatments.Endometrial cancer can be divided into two distinct subtypes (2). Type I tumors occur in younger patients exposed to high levels of estrogen unopposed by progesterone. They are typically localized with better response to hormonal therapy. Type II tumors occur in older patients independent of hormonal status. These tumors are more invasive, have a greater propensity for metastatic spread, and are refractory to hormonal treatment. Activation of distinct biologic pathways has been reported in type I vs. type II cancers. Type I tumors are associated with activation of the PI3-kinase pathway, activating mutations of KRAS, mutant β-catenin, an...

show abstract

Section: Dissociated Endometrial Glands Were Highly Enriched For Epitmentioning

confidence: 74%

Cell-autonomous activation of the PI3-kinase pathway initiates endometrial cancer from adult uterine epithelium

Memarzadeh¹,

Zong

Janzen³

et al. 2010

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

View full text Add to dashboard Cite

show abstract

“…However, ES sulfatase activities in cancerous tissues were lower than those in normal endometria and endometrial adenocarcinoma-derived cells, among which the activity was exceedingly high in Ishikawa cells, suggesting that ES sulfatase in Ishikawa cells contributes to the estrogen-dependent growth of these cells. EST Steroid receptors in the endometrial epithelium are known to be involved in the expression of several genes in response to steroid stimulation of endometrial functions related to the implantation of fertilized eggs, and a failure of the steroid-mediated signal transduction pathway is implicated in the progression of endometrial adenocarcinomas, [2][3][4] as well as of breast carcinomas.5-7) Estrogen is a steroid relevant to the progression of transformed cells, but its active form, 17β-estradiol (E2), is locally generated by several enzymes, such as estrogen sulfotransferase (EST), estrogen sulfate (ES) sulfatase, aromatase, 17β-hydroxysteroid dehydrogenase and so on, since the circulating estrogen in human sera comprises inactive estrone (E1) sulfate.8) Among these enzymes, EST and ES sulfatase in breast carcinomas have been shown to be involved in the regulation of estrogen activity by forming and cleaving the sulfoconjugate of estrogen to inhibit and promote the binding of estrogen to its receptor, respectively. 9, 10) In this connection, inhibition of sulfotransferase by several chlorinated phenol derivatives, such as 6,6-dichloro-4-nitrophenol and hydroxylated polychlorinated biphenyl, has been shown to enhance the activity of endogenous estrogen, and to be probably implicated in human reproductive disorders and an increased incidence of breast carcinomas.…”

mentioning

confidence: 99%

mentioning

confidence: 99%

“…1) Steroid receptors in the endometrial epithelium are known to be involved in the expression of several genes in response to steroid stimulation of endometrial functions related to the implantation of fertilized eggs, and a failure of the steroid-mediated signal transduction pathway is implicated in the progression of endometrial adenocarcinomas, [2][3][4] as well as of breast carcinomas. [5][6][7] Estrogen is a steroid relevant to the progression of transformed cells, but its active form, 17β-estradiol (E2), is locally generated by several enzymes, such as estrogen sulfotransferase (EST), estrogen sulfate (ES) sulfatase, aromatase, 17β-hydroxysteroid dehydrogenase and so on, since the circulating estrogen in human sera comprises inactive estrone (E1) sulfate.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Estrogen sulfotransferase and sulfatase: Roles in the regulation of estrogen activity in human uterine endometrial carcinomas

Tanaka¹,

Kubushiro²,

Iwamori³

et al. 2003

Cancer Science

View full text Add to dashboard Cite

The regulation of estrogen activity through the formation and cleavage of sulfoconjugates of estrogens is known to be related to the progression and metastasis of estrogen-dependent breast carcinomas, but the involvement of sulfoconjugates in the steroid stimulation of endometrial functions and the progression of endometrial adenocarcinomas is not clearly understood yet. Estrogen sulfotransferase (EST) in the uterine endometria during the follicular phase was more active than during the luteal phase, but estrogen sulfate (ES) sulfatase exhibited lower activity during the follicular phase than during the luteal phase. However, ES sulfatase activities in cancerous tissues were lower than those in normal endometria and endometrial adenocarcinoma-derived cells, among which the activity was exceedingly high in Ishikawa cells, suggesting that ES sulfatase in Ishikawa cells contributes to the estrogen-dependent growth of these cells. EST Steroid receptors in the endometrial epithelium are known to be involved in the expression of several genes in response to steroid stimulation of endometrial functions related to the implantation of fertilized eggs, and a failure of the steroid-mediated signal transduction pathway is implicated in the progression of endometrial adenocarcinomas, [2][3][4] as well as of breast carcinomas.5-7) Estrogen is a steroid relevant to the progression of transformed cells, but its active form, 17β-estradiol (E2), is locally generated by several enzymes, such as estrogen sulfotransferase (EST), estrogen sulfate (ES) sulfatase, aromatase, 17β-hydroxysteroid dehydrogenase and so on, since the circulating estrogen in human sera comprises inactive estrone (E1) sulfate.8) Among these enzymes, EST and ES sulfatase in breast carcinomas have been shown to be involved in the regulation of estrogen activity by forming and cleaving the sulfoconjugate of estrogen to inhibit and promote the binding of estrogen to its receptor, respectively. 9, 10) In this connection, inhibition of sulfotransferase by several chlorinated phenol derivatives, such as 6,6-dichloro-4-nitrophenol and hydroxylated polychlorinated biphenyl, has been shown to enhance the activity of endogenous estrogen, and to be probably implicated in human reproductive disorders and an increased incidence of breast carcinomas. 11) On the contrary, environmental xenoestrogens, such as bisphenol, 4-n-octylphenol, 4-n-nonylphenol, and 17α-ethynylestradiol, which have became ubiquitous in the environment and have been shown to cause a decrease in sperm quality and progression of estrogen-dependent cancers by interacting with the estrogen receptor, are converted to their sulfoconjugates by cytosolic sulfotransferase, resulting in detoxification of the chemicals through abolition of their binding ability to the receptor and in facilitation of their removal from the body through an increase in water solubility.12, 13) Thus, the sulfoconjugation of estrogens and related compounds occurring inside cells plays essential roles in the regulation of estrogen rec...

show abstract

“…Receptors for sex hormones have been identified in several 'hormone-dependent' organs such as breast, endometrium and prostate (Smith et al, 1975;Walsh and Hicks, 1979;Howell et al, 1984). The presence of hormone receptors has been found to correlate with a number of clinicopathological factors and may be of prognostic significance.…”

mentioning

confidence: 99%

Expression of oestrogen and progesterone receptors in gastric cancer: a flow cytometric study

et al. 1999

View full text Add to dashboard Cite

Summary Increased expression of oestrogen (ER) and progesterone (PR) receptors have been reported in gastric adenocarcinoma, although results have been variable. Immunohistochemical staining methodologies, in particular in the detection of ER, have been inconsistent with many tumours being classified ER-negative. In this study we have used flow cytometry to quantify expression of ER and PR in gastric adenocarcinoma and examine their relationships with established prognostic indicators. Cytokeratin-positive cells obtained from tumour biopsies of 50 patients with gastric cancer and ten control patients were labelled with biotinylated ER or PR antibodies followed by streptavidin PE. Flow cytometry was seen to increase the detection of ER levels in gastric cancer with more receptor-positive patients in this study than in results published to date. We believe this is related to the sensitivity of the flow cytometric assay with the detection of small shifts in ER level detected using cytokeratin gating. On analysis, the data showed no significant correlations with tumour stage and grade, and no differences were seen between normal mucosa and gastric cancer samples.

show abstract

Association of Exogenous Estrogen and Endometrial Carcinoma

Cited by 96 publications

References 0 publications

Cell-autonomous activation of the PI3-kinase pathway initiates endometrial cancer from adult uterine epithelium

Cell-autonomous activation of the PI3-kinase pathway initiates endometrial cancer from adult uterine epithelium

Estrogen sulfotransferase and sulfatase: Roles in the regulation of estrogen activity in human uterine endometrial carcinomas

Expression of oestrogen and progesterone receptors in gastric cancer: a flow cytometric study

Contact Info

Product

Resources

About