Signaling by estrogens and tamoxifen in the human endometrium

Gielen, Susanne C.J.P.; Santegoets, Lindy A.M.; Hanifi-Moghaddam, Payman; Burger, Curt W.; Blok, Leen J.

doi:10.1016/j.jsbmb.2008.03.021

Cited by 17 publications

(12 citation statements)

References 28 publications

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“…Furthermore, microarray analysis of endometrial patient tissues revealed that 67% of tamoxifen-regulated genes overlap with estradiol treatment (13). Notably, these investigators found that tamoxifen uses the same set of cell cycle genes as estradiol to promote cell proliferation in endometrial tissue, however, it does so to a lesser extent (57). …”

Section: Tamoxifen-regulated Genes Exhibit An Overlapping But Distmentioning

confidence: 99%

Molecular mechanisms of tamoxifen-associated endometrial cancer (Review)

2015

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Tamoxifen has been prescribed to millions of females for breast cancer prevention or treatment. However, tamoxifen is known to significantly enhance the risk of developing endometrial lesions, including hyperplasia, polyps, carcinomas, and sarcoma. Notably, tamoxifen-associated endometrial cancer often has a poor clinical outcome. Understanding the molecular mechanism of tamoxifen-induced endometrial cancer is essential for developing strategies that minimize tamoxifen’s effects on the endometrium without jeopardizing its breast cancer treatment effects. However, this understanding remains limited. Tamoxifen appears to mediate its effect on endometrial cells through estrogenic and non-genomic pathways, rather than introducing a genomic alteration as a carcinogen. Although tamoxifen functions as an agonist and promotes cell proliferation in endometrial cancer, it also displays antagonist activity towards some estrogen targets. Alterations in estrogen receptor-α and its isoforms, as well as the membrane associated estrogen receptor G protein-coupled receptor 30, have been observed with tamoxifen-exposed endometrial cells, and likely mediate the effects of tamoxifen on endometrial cancer cell proliferation and invasion. In addition, gene profile studies of short-term exposure to tamoxifen indicate that the majority of tamoxifen targets are tamoxifen-specific. However, the tamoxifen regulated gene targets that are involved in mediating the effects of long-term exposure to tamoxifen are not yet fully understood. Recent progress has indicated a potential role of unfolded protein response and mammalian target of rapamycin signaling in tamoxifen-associated endometrial cancer. In the future, studies focusing on long-term effects of tamoxifen exposure are required to understand the molecular mechanisms of tamoxifen-associated endometrial cancer.

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Section: Tamoxifen-regulated Genes Exhibit An Overlapping But Distmentioning

confidence: 99%

Molecular mechanisms of tamoxifen-associated endometrial cancer (Review)

2015

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“…Since all three AIs cause a profound reduction in circulating levels of estrogen, the AE profile is largely predictable and consistent with menopausal symptoms. By contrast, tamoxifen can exhibit both estrogen-agonistic and estrogen-antagonistic effects in different tissues [57,58], resulting in a less predictable AE profile. Some effects of tamoxifen, such as its cholesterol-lowering effects and its effects on some cardiovascular outcomes, such as myocardial infarction [59][60][61][62], may be beneficial.…”

Section: Aromatase Inhibitors: Safety Considerationsmentioning

confidence: 99%

Early recurrence risk: aromatase inhibitors versus tamoxifen

Bria¹,

Carlini²,

Cuppone³

et al. 2010

Expert Review of Anticancer Therapy

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Aromatase inhibitors (AIs) are becoming the hormonal treatment of choice for postmenopausal women with early breast cancer. Large, well-controlled clinical studies have established the efficacy and safety of initial adjuvant therapy with letrozole or anastrozole versus the previous standard of 5 years of adjuvant tamoxifen and support using an AI (exemestane, anastrozole or letrozole) following tamoxifen for 2-3 years (early 'switch' treatment) or 5 years (extended adjuvant treatment). Reducing recurrence risk is a primary goal of adjuvant hormonal therapy. There is an early peak of recurrences 2 years after surgery; most are distant metastases rather than local or regional events. Therefore, treatment strategies such as initial therapy with AIs, which reduce early distant recurrence events, can be expected to improve long-term survival outcomes. Switching to an AI following 2-3 years of initial adjuvant tamoxifen is an effective option for patients unable to begin treatment with an AI.

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“…During the premenopausal period, when estrogen concentrations are high, tamoxifen exerts an antagonist effect, whereas during the postmenopausal period, when estrogen concentrations are low, it exerts an agonist effect (8).…”

Section: Introductionmentioning

confidence: 99%

Differences in estrogen and progesterone receptor expression in endometrial polyps and atrophic endometrium of postmenopausal women with and without exposure to tamoxifen

Leao

Andrade

Vassalo

et al. 2013

Molecular and Clinical Oncology

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Abstract.Postmenopausal women who use tamoxifen present with an increased incidence of endometrial alterations, such as polyps and hyperplasia, in addition to a higher risk of malignant endometrial neoplasms. Among these endometrial changes, polyps are the most common, with a pathogenesis associated with hormonal influence. The objective of this study was to compare the expression of estrogen receptors (ERs) and progesterone receptors (PRs) in endometrial polyps from tamoxifen users with that in endometrial polyps and the atrophic endometrium of postmenopausal tamoxifen non-users. Among women undergoing surgical hysteroscopy, 84 tamoxifen users with benign endometrial polyps were selected. This group was compared to 84 samples of atrophic endometrium and to 252 benign polyps from postmenopausal women who were not treated with tamoxifen. The expression of ER̸PR was assessed by immunohistochemical analysis, according to the percentage of stained cells, intensity of nuclear staining and final score. The polyps from tamoxifen users exhibited a higher expression of ER and PR in the glandular epithelium and stroma compared to the atrophic endometrium (P<0.0001). Compared to the polyps from women not treated with tamoxifen, tamoxifen users exhibited a higher PR expression in the epithelium (P=0.0014) and stroma (P=0.0056), with no difference in the expression of ER. In conclusion, endometrial polyps frequently exhibit an increase in ER expression, regardless of tamoxifen use. High levels of PR expression appear to be consistent with the estrogen agonist effects of tamoxifen.

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Signaling by estrogens and tamoxifen in the human endometrium

Cited by 17 publications

References 28 publications

Molecular mechanisms of tamoxifen-associated endometrial cancer (Review)

Molecular mechanisms of tamoxifen-associated endometrial cancer (Review)

Early recurrence risk: aromatase inhibitors versus tamoxifen

Differences in estrogen and progesterone receptor expression in endometrial polyps and atrophic endometrium of postmenopausal women with and without exposure to tamoxifen

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