Risk of Endometrial Cancer After Tamoxifen Treatment of Breast Cancer

Leeuwen, Flora E. van; Benraadt, J.; Willem, Jan; Coebergh, Jan Willem; Kiemeney, Lambertus A.; Gimbrère, Charles H. F.; Otter, Renée; Schouten, Leo J.; Damhuis, Ronald; Bontenbal, M.; Diepenhorst, Fred W.; Belt-Dusebout, Alexandra W. van den; Tinteren, Harm van

doi:10.1097/00006254-199409000-00017

Cited by 65 publications

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“…Endometrial safety is an important issue in women receiving tamoxifen treatment 9 . As expected, 33 there was an initial increase in endometrial thickness in both groups in our study.…”

Section: Discussionsupporting

confidence: 85%

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The effect of tibolone in postmenopausal women receiving tamoxifen after surgery for breast cancer: a randomised, double‐blind, placebo‐controlled trial

Kroiss

Fentiman

Helmond³

et al. 2005

BJOG

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Objective To assess the effects of tibolone on climacteric symptoms, endometrium and serum lipid/ lipoproteins in postmenopausal women receiving tamoxifen after surgery for breast cancer. Design Double-blind, randomised, placebo-controlled, multicentre pilot study.Setting Hospital outpatient clinic.Sample Seventy postmenopausal women receiving tamoxifen following surgery for early breast cancer.Methods Women received 20 mg/day oral tamoxifen plus either 2.5 mg/day oral tibolone or placebo for 12 months. Main outcome measures Frequency and severity of hot flushes (diary cards); intensity of hot flushes and sweats (Landgren scale); interference of hot flushes and sweats with normal life; frequency and intensity of other climacteric symptoms; endometrial thickness and histology; vaginal bleeding; breast cancer recurrence and serum lipid/lipoproteins. Results Daily card data showed no change in the daily number of hot flushes with either tibolone or placebo (P ¼ 0.219) after three months. There was a significant reduction in the severity of flushes with tibolone compared with placebo (À0.4 vs 0.2, P ¼ 0.031). The Landgren scale showed a mean change in the number of hot flushes of À0.6 with tibolone and þ1.1 with placebo after 12 months (P ¼ 0.022). Endometrial biopsies were normal and vaginal bleeding was similar in both groups. A significant decrease in triglycerides (À23% vs 1.4%) and HDL (À12% vs 19%) was seen with tibolone compared with placebo after 12 months. Conclusions Tibolone prevented an increase in hot flushes in postmenopausal women given tamoxifen following surgery for breast cancer without untoward effects on the endometrium. Beneficial effects on serum lipid profile were noted.

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“…Endometrial safety is an important issue in women receiving tamoxifen treatment 9 . As expected, 33 there was an initial increase in endometrial thickness in both groups in our study.…”

Section: Discussionsupporting

confidence: 85%

“…This third metabolite also exerts local progestogenic effects in the endometrium and prevents endometrial stimulation 7 . Tamoxifen acts as an oestrogen agonist on endometrial cells, 8 and causes endometrial stimulation which may lead to endometrial hyperplasia or cancer 9 …”

Section: Introductionmentioning

confidence: 99%

The effect of tibolone in postmenopausal women receiving tamoxifen after surgery for breast cancer: a randomised, double‐blind, placebo‐controlled trial

Kroiss

Fentiman

Helmond³

et al. 2005

BJOG

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“…Although GBH did not produce a positive uterotrophic assay, the lowest dose of GBH increased the height of luminal epithelial cells which is a well‐recognized morphological estrogenic uterine response (Padilla‐Banks et al, ). This result has an important relevance due to the stimulation of the uterine luminal epithelium height that has been associated with uterine disorders, such as endometriosis and endometrial carcinoma (van Leeuwen et al, ).…”

Section: Discussionmentioning

confidence: 99%

“…Gasnier et al () showed inhibition of the transcription activities of ERα and ERβ in HepG2 cells by a GBH formulation. Keeping in mind that both ERs are fundamental for a normal uterine function and that ERα deregulation has been associated with uterine disorders (endometriosis or endometrial carcinoma) (van Leeuwen et al, ); more studies are needed to assess whether GBH exposure could have a negative impact on reproductive performance or a higher predisposition to those pathologies. PR is a nuclear receptor for progesterone, a classical estrogen‐regulated protein, and a transcription factor.…”

Section: Discussionmentioning

confidence: 99%

Effects of a glyphosate‐based herbicide on the uterus of adult ovariectomized rats

Varayoud

Durando

Ramos

et al. 2016

Environmental Toxicology

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Glyphosate is the active ingredient of several herbicide formulations. Different reports suggest that glyphosate-based herbicides (GBHs) may act as endocrine disruptors. We evaluated the potential estrogenic effects of a GBH formulation using the uterotrophic assay. Adult ovariectomized rats were sc injected for 3 consecutive days with: saline solution (vehicle control), 2.10 g E /kg/day (uterotrophic dose; UE ), 2.10 g E /kg/day (nonuterotrophic dose; NUE ), or 0.5, 5, or 50 mg GBH/kg/day of the. Twenty-four hours after the last injection, the uterus was removed and weighed and processed for histopathology and mRNA extraction. Epithelial cell proliferation and height and expression of estrogen-responsive genes were evaluated (estrogen receptors, ERα and ERβ; progesterone receptor, PR; complement 3, C3). Uterine weight and epithelial proliferation were not affected by GBH. However, the luminal epithelial cell height increased at GBH0.5. ERα mRNA was downregulated by all GBH doses and E groups, whereas PR and C3 mRNA were diminished by GBH0.5. GBH5-, GBH50-, and UE -treated rats showed downregulated ERα protein expression in luminal epithelial cells, while the receptor was upregulated in the stroma. GBH upregulated ERβ (GBH0.5-50) and PR (GBH5) expressions in glandular epithelial cells, similar effect to that of NUE group. These results indicate that, although the uterine weight was not affected, GBH modulates the expression of estrogen-sensitive genes. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1191-1201, 2017.

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“…Because TAM is known to block the binding of E 2 to its receptor, this anti‐estrogen action is believed to be the underlying mechanism for the efficacy of TAM in breast cancer therapy. However, this single mode of action of TAM is inadequate in explaining the fact that TAM is also known to induce endometrial 39−42 and possibly other 43−45 cancers. Recent studies indicate that after metabolic activation, TAM is able to bind to DNA, forming DNA adducts 45 .…”

Section: β‐Estradiol Epoxidation As a Molecular Basis For Breast Camentioning

confidence: 99%

17β‐Estradiol epoxidation as the molecular basis for breast cancer initiation and prevention

2002

Asia Pac J Clin Nutr

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Epidemiological and animal studies have indicated that 17beta-estradiol (E2) is involved in breast cancer; however, the mechanism is unclear. We found that E2 could be activated by epoxidation, resulting in its ability to inhibit nuclear DNA-dependent RNA synthesis, and to bind DNA, forming DNA adducts both in vitro and in vivo. Because epoxidation is required for the activation of many chemical carcinogens, including benzo(a)pyrene, 7,12-dimethylbenz(a)anthracene and aflatoxins, we proposed previously that E2 epoxidation is the underlying mechanism for the initiation of breast cancer. The first part of this review is to present the experimental evidence obtained from this laboratory in support of this hypothesis. Based on these newly discovered insights on E2 epoxidation and its initiation role in breast cancer carcinogenesis, a method to screen chemopreventive agents against breast cancer has been developed. This constitutes the second part of the review. Two examples will be used to illustrate the utility of this screening technique. The effect of fat on breast cancer has been a longstanding but unresolved issue. Epidemiological studies provide conflicting results regarding the association of dietary fat and breast cancer. Because vegetable oils contain various amount of mono- and polyunsaturated fatty acids, they are potential antioxidants. Data are presented to show that commercial vegetable oils, independent of their mono- or polyunsaturated fatty acid content, are all able to prevent the formation of E2 epoxide, as measured by the loss of the ability of E2 to inhibit nuclear RNA synthesis in vitro. Tamoxifen (TAM), an anti-estrogen used for breast cancer treatment, has recently been found to have a strong breast cancer preventive effect. The mechanism for this is unknown. Using the same screening technique, we found that when incubated together with E2 for epoxidation, TAM was able to prevent the formation of E2 epoxide, as evidenced by both the loss of the ability of E2 to inhibit nuclear RNA synthesis and the reduced binding of [3H]-labelled E2 to nuclear DNA in a dose-dependent manner. These experimental results suggest that the breast cancer preventive effect of TAM is to prevent the formation of E2 epoxide through a competitive epoxidation mechanism with E2.

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Risk of Endometrial Cancer After Tamoxifen Treatment of Breast Cancer

Cited by 65 publications

References 0 publications

The effect of tibolone in postmenopausal women receiving tamoxifen after surgery for breast cancer: a randomised, double‐blind, placebo‐controlled trial

The effect of tibolone in postmenopausal women receiving tamoxifen after surgery for breast cancer: a randomised, double‐blind, placebo‐controlled trial

Effects of a glyphosate‐based herbicide on the uterus of adult ovariectomized rats

17β‐Estradiol epoxidation as the molecular basis for breast cancer initiation and prevention

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