Comparative temporal and dose-dependent morphological and transcriptional uterine effects elicited by tamoxifen and ethynylestradiol in immature, ovariectomized mice

Fong, C. J.; Burgoon, Lyle D.; Williams, Kurt J.; Forgacs, Agnes L.; Zacharewski, Timothy R.

doi:10.1186/1471-2164-8-151

Cited by 37 publications

(40 citation statements)

References 80 publications

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“…Indeed, recent transcriptome data indicated that IL4I1 mRNA expression could be induced in the uterus of mice by administration of ethynylestradiol. 14 In accordance with its normal pattern of expression, IL4I1 was more frequently detected in B-cell lymphoid malignancies, not only in infiltrating macrophages, but also in lymphoma cells of cHL and NLPHL, SLL/CLL, follicular lymphoma and PMBL. In follicular lymphoma, these observations were confirmed by measurement of the enzymatic activity on sorted CD19-positive and CD19-negative cell populations.…”

Section: Resultsmentioning

confidence: 72%

The novel immunosuppressive enzyme IL4I1 is expressed by neoplastic cells of several B-cell lymphomas and by tumor-associated macrophages

et al. 2009

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We previously reported a strong IL4I1 gene expression in primary mediastinal B-cell lymphoma (PMBL) and recently identified the protein as a secreted L-phenylalanine oxidase, physiologically expressed by myeloid cells, which inhibits T-cell proliferation in vitro. Here, we analyzed the pattern of IL4I1 protein expression in 315 human lymphoid and nonlymphoid malignancies. Besides PMBL, IL4I1 expression in tumors was very frequent. IL4I1 was detected in tumorassociated macrophages from most of the tumors and in neoplastic cells from follicular lymphoma, classic and nodular lymphocyte predominant Hodgkin lymphomas and small lymphocytic lymphoma, three of which are germinal center derived. IL4I1-positive tumor cells were also detected in rare cases of solid cancers, mainly mesothelioma. The enzymatic activity paralleled protein expression, suggesting that IL4I1 is functional in vivo. Depending on the tumor type, IL4I1 may impact on different infiltrating lymphocyte populations with consequences on tumor evolution. In the particular case of follicular lymphoma cells, which are susceptible to antitumor cytotoxic T cells killing but depend on interactions with local T helper cells for survival, a high level of IL4I1 expression seems associated with the absence of bone marrow involvement and a better outcome. These findings plead for an evaluation of IL4I1 as a prognosis factor.

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Section: Resultsmentioning

confidence: 72%

The novel immunosuppressive enzyme IL4I1 is expressed by neoplastic cells of several B-cell lymphomas and by tumor-associated macrophages

et al. 2009

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“…The histologic appearance ( Supplementary Fig. S2) showed that tamoxifen caused an increase of uterine glands and epithelial height as well as enlargement of the stromal compartment (27). We found that the level of VEGF protein in the uterus was upregulated in a dosedependent manner ( Fig.…”

Section: Short-term Tamoxifen Treatment Modulates Uterine Vegf/pedf Bmentioning

confidence: 60%

“…To study the subacute effect we used the short-term treatment model, which demonstrated a dose-dependent increase of uterine weight (Fig. 1A), as described in the literature (27). The histologic appearance ( Supplementary Fig.…”

Section: Short-term Tamoxifen Treatment Modulates Uterine Vegf/pedf Bmentioning

confidence: 99%

Pigment Epithelium–Derived Factor Alleviates Tamoxifen-Induced Endometrial Hyperplasia

Goldberg

Bar‐Joseph

Grossman

et al. 2015

Molecular Cancer Therapeutics

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Tamoxifen is a cornerstone component of adjuvant endocrine therapy for patients with hormone-receptor-positive breast cancer. Its significant adverse effects include uterine hyperplasia, polyps, and increased risk of endometrial cancer. However, the underlying molecular mechanism remains unclear. Excessive angiogenesis, a hallmark of tumorigenesis, is a result of disrupted balance between pro-and anti-angiogenic factors. VEGF is a proangiogenic factor shown to be elevated by tamoxifen in the uterus. Pigment epithelium-derived factor (PEDF) is a potent anti-angiogenic factor that suppresses strong pro-angiogenic factors, such as VEGF. Our aim was to investigate whether angiogenic balance plays a role in tamoxifen-induced uterine pathologies, elucidate the molecular impairment in that network, and explore potential intervention to offset the proposed imbalance elicited by tamoxifen. Using in vivo mouse models, we demonstrated that tamoxifen induced a dose-dependent shift in endogenous uterine angiogenic balance favoring VEGF over PEDF. Treatment with recombinant PEDF (rPEDF) abrogated tamoxifen-induced uterine hyperplasia and VEGF elevation, resulting in reduction of blood vessels density. Exploring the molecular mechanism revealed that tamoxifen promoted survival and malignant transformation pathways, whereas rPEDF treatment prevents these changes. Activation of survival pathways was decreased, demonstrated by reduction in AKT phosphorylation concomitant with elevation in JNK phosphorylation. Estrogen receptor-a and c-Myc oncoprotein levels were reduced. Our findings provide novel insight into the molecular mechanisms tamoxifen induces in the uterus, which may become the precursor events of subsequent endometrial hyperplasia and cancer. We demonstrate that rPEDF may serve as a useful intervention to alleviate the risk of tamoxifen-induced endometrial pathologies.

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“…TAM induces uterotrophy in immature and ovariectomized rodents and elicits a gene expression profile similar to estrogen in uterine tissue, albeit with lower efficacy (Hodges et al 2003, Frasor et al 2004, Fong et al 2007, Kwekel et al 2009). Despite TAM exhibiting partial ER-agonist activity in the uterus, there are significant differences between TAM and full agonists.…”

Section: Introductionmentioning

confidence: 99%

“…TAM lacks the stimulation of water imbibition that is clearly induced in the presence of 17b-estradiol (E 2 ) and 17a-ethynylestradiol (EE; Reel et al 1996). Moreover, numerous studies report unique gene expression changes elicited by TAM (Pole et al 2005, Fong et al 2007, Kwekel et al 2009.…”

Section: Introductionmentioning

confidence: 99%

Effects of tamoxifen and ethynylestradiol cotreatment on uterine gene expression in immature, ovariectomized mice

Fong

Burgoon

Williams³

et al. 2010

Journal of Molecular Endocrinology

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Tamoxifen (TAM), the primary treatment for estrogen receptor (ER)-positive breast cancer, has been associated with an increased incidence of endometrial cancer in postmenopausal, but not premenopausal women. TAM elicits a partial ER-mediated uterotrophic response in immature rodents when compared with ethynylestradiol (EE), a potent ER agonist. However, cotreatment with 1000 mg/kg TAM antagonizes the uterotrophic effect induced by 30 mg/kg EE. To further investigate the anti-uterotrophic activity of TAM, immature, ovariectomized C57BL/6 mice were treated with a single oral dose of EE, TAM, EECTAM, or vehicle, and harvested at 2, 4, 8, 12, 18, and 24 h or after three daily treatments at 72 h. Significant increases in uterine wet weight (UWW) were observed at 18 h for EE, TAM, and the mixture. However, mixture induction of UWW was significantly lower when compared with EE-induced uterotrophy at 72 h. This inhibitory effect is also reflected in decreases in luminal circumference, yet EE-induced luminal epithelial cell height was unaffected by cotreatment with TAM. Gene expression analysis using a 2!2 factorial cDNA microarray study design identified 2518 differentially expressed genes following EE treatment alone. However, only 290 EE-elicited gene expression changes were affected by TAM cotreatment, in a manner consistent with the anti-estrogenic response. These data suggest that TAM antagonism of EE-induced UWW increase involves the selective inhibition of EE-induced genes.

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Comparative temporal and dose-dependent morphological and transcriptional uterine effects elicited by tamoxifen and ethynylestradiol in immature, ovariectomized mice

Cited by 37 publications

References 80 publications

The novel immunosuppressive enzyme IL4I1 is expressed by neoplastic cells of several B-cell lymphomas and by tumor-associated macrophages

The novel immunosuppressive enzyme IL4I1 is expressed by neoplastic cells of several B-cell lymphomas and by tumor-associated macrophages

Pigment Epithelium–Derived Factor Alleviates Tamoxifen-Induced Endometrial Hyperplasia

Effects of tamoxifen and ethynylestradiol cotreatment on uterine gene expression in immature, ovariectomized mice

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