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Pigment Epithelium–Derived Factor Alleviates Tamoxifen-Induced Endometrial Hyperplasia

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Pigment Epithelium–Derived Factor Alleviates Tamoxifen-Induced Endometrial Hyperplasia Published OnlineFirst October 8, 2015; DOI: 10.1158/1535-7163.MCT-15-0523 Cancer Biology and Signal Transduction Molecular Cancer Therapeutics Pigment Epithelium–Derived Factor Alleviates Tamoxifen-Induced Endometrial Hyperplasia Keren Goldberg1, Hadas Bar-Joseph1, Hadas Grossman1, Noa Hasky1, Shiri Uri-Belapolsky1, Salomon M. Stemmer2, Dana Chuderland1, Ruth Shalgi1, and Irit Ben-Aharon2 Abstract Tamoxifen is a cornerstone component of adjuvant endocrine angiogenic balance favoring VEGF over PEDF. Treatment with therapy for patients with hormone-receptor–positive breast can- recombinant PEDF (rPEDF) abrogated tamoxifen-induced uter- cer. Its significant adverse effects include uterine hyperplasia, ine hyperplasia and VEGF elevation, resulting in reduction of polyps, and increased risk of endometrial cancer. However, the blood vessels density. Exploring the molecular mechanism underlying molecular mechanism remains unclear. Excessive revealed that tamoxifen promoted survival and malignant trans- angiogenesis, a hallmark of tumorigenesis, is a result of disrupted formation pathways, whereas rPEDF treatment prevents these balance between pro- and anti-angiogenic factors. VEGF is a pro- changes. Activation of survival pathways was decreased, demon- angiogenic factor shown to be elevated by tamoxifen in the uterus. strated by reduction in AKT phosphorylation concomitant with Pigment epithelium–derived factor (PEDF) is a potent anti-angio- elevation in JNK phosphorylation. Estrogen receptor-a and c-Myc genic factor that suppresses strong pro-angiogenic factors, such as oncoprotein levels were reduced. Our findings provide novel VEGF. Our aim was to investigate whether angiogenic balance insight into the molecular mechanisms tamoxifen induces in the plays a role in tamoxifen-induced uterine pathologies, elucidate uterus, which may become the precursor events of subsequent the molecular impairment in that network, and explore potential endometrial hyperplasia and cancer. We demonstrate that rPEDF intervention to offset the proposed imbalance elicited by tamox- may serve as a useful intervention to alleviate the risk of tamox- ifen. Using in vivo mouse models, we demonstrated that tamox- ifen-induced endometrial pathologies. Mol Cancer Ther; 14(12); ifen induced a dose-dependent shift in endogenous uterine 2840–9. Ó2015 AACR. Introduction Tamoxifen belongs to a class of selective estrogen receptor modulators (SERM), it binds to estrogen receptor (ER) and elicits Tamoxifen is considered a pivotal component of the hormonal estrogen agonistic or antagonistic responses by recruiting diverse therapy backbone commonly used for treatment of patients with sets of corepressors and coactivators, depending on the target hormone-receptor–positive breast cancer in all settings—adju- tissue (4). Tamoxifen serves as antagonist to ER in breast cancer vant, metastatic, and as a "primary prevention" risk-reducing cells, whereas in the uterus it exerts partial agonistic activity, strategy for high-risk populations (1, 2). The current American resulting in a range of endometrial pathologies including hyper- Society of Clinical Oncology guidelines for adjuvant hormonal plasia, polyps, carcinomas, and sarcomas (5, 6). Several large- therapy by tamoxifen have been recently revised; for premeno- scale studies have reported a 2- to 7-fold increase in the incidence pausal patients for 10 years of adjuvant tamoxifen therapy rather of endometrial cancer in patients treated with tamoxifen (7, 8) than 5 years (3), whereas in postmenopausal patients aromatase compared with control patients. Histopathologic changes in the inhibitors are considered an alternative, though tamoxifen repre- endometrium were observed after tamoxifen administration sents a valid and effective treatment standard. mainly in postmenopausal patients (9), and because endometrial hyperplasia is viewed as a possible precursor for malignant transformation, patients with atypical hyperplasia are closely monitored. 1Department of Cell and Developmental Biology, Sackler Faculty of Tamoxifen is known to exert its effect on the endometrium via 2 Medicine, Tel Aviv University, Tel Aviv, Israel. Institute of Oncology, activation of estrogen-regulated genes (10); however, recent Davidoff Center and Rabin Medical Center, Petah-Tiqva and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. observations indicate that tamoxifen can also activate different Note: Supplementary data for this article are available at Molecular Cancer sets of genes that are not regulated by estrogen (11). As demon- fi Therapeutics Online (http://mct.aacrjournals.org/). strated by gene array pro ling, these genes are related to cellular processes of DNA replication, cell-cycle progression, and cellular D. Chuderland, R. Shalgi, and I. Ben-Aharon contributed equally to this article. organization (12). Yet, the exact molecular mechanism by which This work was performed in partial fulfillment of the requirements for a PhD tamoxifen exerts adverse effects on the uterus remains to be degree of K. Goldberg, Sackler Faculty of Medicine, Tel Aviv University, Israel. elucidated. Corresponding Author: Irit Ben-Aharon, Institute of Oncology, Davidoff Center, Angiogenesis, or formation of new blood vessels, is essential for Rabin Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Kaplan tissue proliferation. Under physiologic conditions, endometrial St., Petach-Tiqva 49100, Israel. E-mail: [email protected] angiogenesis is tightly regulated by pro- and anti-angiogenic doi: 10.1158/1535-7163.MCT-15-0523 factors (13); estrogen plays a pivotal role in establishing new Ó2015 American Association for Cancer Research. vascular bed and promoting cellular growth and differentiation 2840 Mol Cancer Ther; 14(12) December 2015 Downloaded from mct.aacrjournals.org on September 29, 2021. © 2015 American Association for Cancer Research. Published OnlineFirst October 8, 2015; DOI: 10.1158/1535-7163.MCT-15-0523 PEDF Alleviates Tamoxifen-Induced Endometrial Hyperplasia within the endometrium at each menstrual cycle (13). In ovari- in canola oil. Tamoxifen was administered per os by a ectomized mice, tamoxifen stimulates production of uterine blunt gavage needle. Control mice were administered with VEGF (14), one of the major pro-angiogenic factors in the endo- canola oil. metrium, known to be upregulated in many pathologies and malignancies (15). Ovariectomy Pigment epithelium–derived factor (PEDF) is a 50-kDa glyco- Mice were anesthetized by an intraperitoneal injection of a protein that belongs to the noninhibitory members of the serine mixture of ketamine hydrochloride (Kepro) and xylazine hydro- protease inhibitors (serpin) superfamily. PEDF is one of the most chloride (VMD). The dorsal mid-lumbar area was shaved to potent physiologic inhibitors of angiogenesis (16). The anti- remove hair and prepared for aseptic surgery. A single skin angiogenic effect of PEDF is associated with disruption of endo- incision at the dorsal end of the ribcage was made and muscle thelial proliferation, promotion of endothelial cell apoptosis, and wall was incised, exposing the peri-ovarian fat pad region. The downregulation of pro-angiogenic factors. Increasing amount of ovary was exteriorized by grasping the peri-ovarian fat with tissue evidence indicates that under physiologic conditions, an essential forceps; the oviduct area was ligated and cauterized by extremely balance between PEDF and VEGF exists, and PEDF may counter- hot forceps to avoid bleeding, thus excising the ovary. act the angiogenic potential of VEGF (17). Several studies showed The remaining tissue was returned into the peritoneal cavity. The that PEDF level declines with age, and suggested that this decline procedure was repeated at the other side as well. The muscle may play a key role in the development of angiogenic-related incisions were closed with 4-0 absorbable suture (Ethicon) and pathologies (18). Moreover, it was shown that decrease in PEDF skin incisions were closed with wound clips (Clay-Adams). Mice expression is one of the mechanisms that promote tumor growth were allowed to rest for one week to ensure post-menopausal (19), suggesting PEDF as an anticancer therapy (20, 21). We have state, before experimental onset. recently characterized the expression and regulation of PEDF in human and rodent premenopausal endometrium, indicating that RNA isolation, reverse transcription, and qRT-PCR PEDF is dynamically expressed in mice endometrium throughout RNA was extracted using Trizol reagent (Invitrogen), accord- the estrous cycle, in reciprocity to VEGF, and that the balance ing to the manufacturer's instructions, and quantified with the between the two is regulated by estrogen and progestrone (22, Nano-Drop spectrophotometer (ND-1000; Thermo Scientific). 23). PEDF is a secreted glycoprotein that promotes a variety of Total RNA was reverse transcribed using high capacity cDNA activities upon binding to various receptors (20). In our previous reverse transcription kit (Applied Biosystems; ABI). Changes in studies, we showed that endometrial cells express Patatin-like the level of mRNA expression were detected by SYBR green phospholipase domain-containing protein 2 (PNPLA2; ref. 22), a reagent (SYBR Green PCR Master Mix, Applied Biosystems) PEDF receptor (PEDF-R) that mediates mainly prosurvival activity using 20-ng cDNA and specific primers, on an ABI Prism 7900 (24). Another key protein that regulates the anti-angiogenic Sequence PCR machine (Applied Biosystems).
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