The effects of tamoxifen on proliferation and steroid receptor expression in postmenopausal endometrium

Mourits, Marian J.E.; Hoor, KA Ten; Zee, van der Ate; Willemse, Phb; Vries, de Elisabeth G. E.; Hollema, Harmen

doi:10.1136/jcp.55.7.514

Cited by 43 publications

(31 citation statements)

References 37 publications

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“…These findings are consistent with those of other studies demonstrating a higher ER expression in the polyps from tamoxifen non-users compared to that in the adjacent atrophic endometrium (15,23).…”

Section: Discussionsupporting

confidence: 93%

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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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Section: Discussionsupporting

confidence: 93%

“…Previous studies comparing polyps from tamoxifen users to those from non-users have reported lower ER expression and increased PR expression in tamoxifen users, demonstrating an agonist effect of tamoxifen on the endometrium. However, only few small case studies are available, reporting variable results (21)(22)(23)(24).…”

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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“…In contrast, the expression of inhibin/ activin a and b in polyps was found to be similar in both groups (Mylonas et al 2004). Furthermore, the apoptosis/proliferation index, determined by measuring the proliferation marker Ki67 and the apoptosis markers Fas, FasL and Bcl-2, is higher in benign endometria of tamoxifen users compared with endometria of non-users (Mourits et al 2002a(Mourits et al , 2002b.…”

Section: Introductionmentioning

confidence: 71%

Tamoxifen treatment for breast cancer enforces a distinct gene-expression profile on the human endometrium: an exploratory study

Gielen¹,

Kühne²,

Ewing³

et al. 2005

Endocr Relat Cancer

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Tamoxifen treatment for breast cancer increases proliferation of the endometrium, resulting in an enhanced prevalence of endometrial pathologies, including endometrial cancer. An exploratory study was performed to begin to understand the molecular mechanism of tamoxifen action in the endometrium. Gene-expression profiles were generated of endometrial samples of tamoxifen users and compared with matched controls. The pathological classification of samples from both groups included atrophic/inactive endometrium and endometrial polyps. Unsupervised clustering revealed that samples of tamoxifen users were, irrespective of pathological classification, fairly similar and consequently form a subgroup distinct from the matched controls. Using SAM analysis (a statistical method to select genes differentially expressed between groups), 256 differentially expressed genes were selected between the tamoxifen and control groups. Upon comparing these genes with oestrogen-regulated genes, identified under similar circumstances, 95% of the differentially expressed genes turned out to be tamoxifen-specific. Finally, construction of a gene-expression network of the differentially expressed genes revealed that 69 genes centred around five well-known genes: TP53, RELA, MYC, epidermal growth factor receptor and b-catenin. This could indicate that these well-known genes, and the pathways in which they function, are important for tamoxifencontrolled proliferation of the endometrium.

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“…In a small subset of women with available endometrial tissue, however, tamoxifen addition induced a higher proliferation of both glandular and stromal compartments relative to anastrozole alone. Yet, the expression of Ki-67 in the endometrial gland was as low as 2% to 3%, much lower than that observed in normal endometrium adjacent to endometrial cancer (34), or under treatment with 20 mg/d tamoxifen in hyperplastic or premalignant tissue (35,36), suggesting that the addition of low-dose tamoxifen should not lead to an increased risk of endometrial cancer. CYP2D6 genotype did not influence endometrial thickness changes under tamoxifen, but the power of this observation is too limited to draw reliable conclusions.…”

Section: Discussionmentioning

confidence: 97%

Randomized Biomarker Trial of Anastrozole or Low-Dose Tamoxifen or Their Combination in Subjects with Breast Intraepithelial Neoplasia

Bonanni

Serrano

Gandini

et al. 2009

Clinical Cancer Research

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Purpose: In the Anastrozole, Tamoxifen Alone or in Combination trial, the combination arm was inferior to anastrozole alone in terms of disease-free survival possibly due to an adverse pharmacokinetic interaction or a predominant estrogenic effect of tamoxifen under estrogen deprivation. We assessed whether the addition of a lower dose of tamoxifen influenced anastrozole bioavailability and favorably modulated biomarkers of bone fracture, breast cancer, cardiovascular disease, and endometrial cancer risk. The influence of CYP2D6 genotype on tamoxifen effects was also determined. Experimental Design: Seventy-five postmenopausal women with breast intraepithelial neoplasia were randomly allocated to either 1 mg/d anastrozole or 10 mg/wk tamoxifen or their combination for 12 months. Study endpoints were plasma drug concentrations and changes of C-telopeptide, osteocalcin, estradiol/sex hormone binding globulin (SHBG) ratio, estrone sulfate, insulin-like growth factor-I (IGF-I)/insulin-like growth factor binding protein-3 (IGFBP-3), C-reactive protein, antithrombin-III, endometrial Ki-67 expression, and thickness. Results: Anastrozole concentrations were not affected by the combination with lowdose tamoxifen, whereas endoxifen levels were lower in poor CYP2D6 metabolizers. C-telopeptide increased by 20% with anastrozole and decreased by 16% with tamoxifen and by 7% with their combination (P < 0.001); osteocalcin showed similar changes. Compared with anastrozole, the combination arm showed lower IGF-I/IGFBP-3 levels (-17% versus -9%; P = 0.004) and lower estradiol/SHBG and estrone sulfate reductions (-15% versus -29% and -30% versus 38%, respectively). However, IGF-I/IGFBP-3 and estradiol/SHBG did not decrease in poor CYP2D6 metabolizers. Endometrial thickness was not greater in the combination than in the anastrozole arm. Conclusions: The addition of a weekly tamoxifen administration did not impair anastrozole bioavailability and modulated favorably its safety profile, providing the rationale for further studies. (Clin Cancer Res 2009;15(22):7053-60) Aromatase inhibitors are a standard treatment of estrogen receptor-positive breast cancer in postmenopausal patients (1-4) and are being tested as chemopreventive agents in at-risk women (5). However, these agents are associated with increased bone fracture rate, joint and tendon disorders, and possibly increased cardiovascular risk due to their profound estrogen-suppressive effect rising concern on their long-term safety, especially in the prevention setting. Moreover, prolonged aromatase inhibitor treatment may lead to the onset of endocrine resistance with the emergence of estrogen hypersensitive cell clones (6). One potential way to counteract these phenomena is to add tamoxifen to exploit its partial estrogenicity. In the Anastrozole, Tamoxifen Alone or in Combination study, a phase III adjuvant trial with three arms (1 mg anastrozole, 20 mg tamoxifen, and their combination), anastrozole significantly prolonged disease-free survival versus tamoxifen. Mor...

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The effects of tamoxifen on proliferation and steroid receptor expression in postmenopausal endometrium

Cited by 43 publications

References 37 publications

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

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

Tamoxifen treatment for breast cancer enforces a distinct gene-expression profile on the human endometrium: an exploratory study

Randomized Biomarker Trial of Anastrozole or Low-Dose Tamoxifen or Their Combination in Subjects with Breast Intraepithelial Neoplasia

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