Histopathologic behavior of endometrial hyperplasia during tamoxifen therapy for breast cancer

Garuti, Giancarlo; Cellani, Fulvia; Centinaio, Giovanna; Sita, Giulia; Nalli, G; Luerti, Massimo

doi:10.1016/j.ygyno.2005.10.010

Cited by 16 publications

(9 citation statements)

References 19 publications

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“…In a recent study, the baseline hysteroscopic assessment revealed an incidence of 31.3% of overall endometrial morbidity in asymptomatic postmenopausal ERα+ breast cancer patients (9). For patients who have endometrial conditions such as hyperplasia without atypia prior to tamoxifen treatment, the rate of progression to more advanced stage endometrial lesions is almost 50% after 24 months of tamoxifen administration (10). …”

Section: Introductionmentioning

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: Introductionmentioning

confidence: 99%

Molecular mechanisms of tamoxifen-associated endometrial cancer (Review)

2015

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“…Tamoxifen is a potent E‐antagonist on breast tissue and is accredited for the prevention of breast cancer 11 . However, its E‐agonist action on the endometrium and the resultant increased risk for hyperplasia–cancer do not qualify this molecule as an alternative to HT for prolonged administration 12 . Toremifene is an FDA‐approved SERM for the treatment of advanced breast cancer.…”

Section: Introductionmentioning

confidence: 99%

The Cardiovascular Effects of Selective Estrogen Receptor Modulators

Christodoulakos¹,

Lambrinoudaki²,

Botsis³

2006

Annals of the New York Academy of Sciences

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Coronary artery disease (CAD) is the main contributor of mortality among postmenopausal women. Menopause-associated estrogen deficiency has both metabolic and vascular consequences that increase the risk for CAD. Hormone therapy (HT) has been reported to have a beneficial effect on metabolic and vascular factors influencing the incidence of CAD. Although observational studies have reported that HT reduces significantly the risk for CAD, randomized clinical trials (WHI, HERS, ERA) have questioned the efficacy of HT in primary and secondary CAD prevention despite confirming the lipid-lowering effect of HT. In the aftermath of the WHI, increased interest has been given to the action of selective estrogen receptor modulators (SERMs) and their effect on the cardiovascular system. The chemical structure of SERMs, either triphenylethilyn (tamoxifen) or benzothiophene (raloxifene) derivatives, differs from that of estrogens. SERMs are nonsteroidal molecules that bind, with high affinity, to the ER. SERMs induce conformational changes to the ligand-binding domain of the ER that modulate the ability of the ER to interact with coregulator proteins. The relative balance of coregulators within a cell determines the transcriptional activity of the receptor-ligand complex. SERMs therefore may express an estrogen-agonist or estrogen-antagonist effect depending on the tissue targeted. SERMs express variable effects on the metabolic and vascular factors influencing the incidence of CAD. SERMs have been reported to modulate favorably the lipid-lipoprotein profile. Toremifene expresses the most beneficial effect followed by tamoxifene and raloxifene, while ospexifene and HMR-3339 have the least effect and may even increase triglycerides. Raloxifene and tamoxifene decrease serum homocysteine levels and C-reactive proteins (CRP), which are both markers of CAD risk. Raloxifene has been reported to increase the nitric oxide (NO)-endothelin (ET)-1 ratio and, thus, contribute to proper endothelial function and vasodilation. Toremifene has no effect on the NO-ET-1 ratio. Finally, raloxifene decreases the vascular cell adhesion molecules and the inflammatory cytokines TNF-alpha and IL-6. Of the SERMs, raloxifene has had the most extensive evaluation regarding the effect on the vascular wall of endothelium. Although not confirmed by large clinical trials, raloxifene has been reported to have an effect on the cohesion of the intercellular junction (VE-cadherin) and the synthesis-degradation of extracellular matrix (MMP-2). The Multiple Outcomes Raloxifene Evaluation (MORE) study has reported that raloxifene may have a cardioprotective effect when administered to postmenopausal women at high risk for CAD disease.

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“…Under tamoxifen's influence, there is progression of endometrial hyperplasia without atypia to atypical hyperplasia in approximately 50% of cases. 1 In addition, evidence suggests an 8.3% progression rate to become endometrial cancers, far higher than the background expected rate of 1.6%. 2 Notably, tamoxifen-associated endometrial tumours are recognised as having higher mortality than those without exposure to tamoxifen.…”

Section: Introductionmentioning

confidence: 94%