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Fig. S1. In vitro characterization of pre-adipocytes and adipocytes. Fig. S2. Histological analysis of ovaries and oviducts of obese and control mice. Fig. S3. Foxa2, a marker of endometrial glands, staining in the uteri of obese and control mice. Table S1. A list of proteins that are differentially expressed between pre-adipocytes and adipocytes-derived conditioned media. Table S2. The outcome of breeding trials in obese and control mice. Table S3. Human endometrial cancer patient information

Obesity is responsible for increased morbidity and mortality in endometrial cancer. Despite the positive correlation of body mass index (BMI) or obesity in endometrial carcinogenesis, the contribution of adipose tissue to the pathogenesis of endometrial hyperplasia and cancer is unclear. This study clarifies the role of adipocytes in the pathogenesis of endometrial cancer by demonstrating that adipocyte-conditioned medium (ACM) increases proliferation, migration, and survival of endometrial cancer cells compared with preadipocyte-conditioned medium (PACM). Comparative cytokine array analysis of ACM and PACM reveal upregulation of a group of cytokines belonging to the VEGF signaling pathway in ACM. VEGF protein expression is upregulated in visceral adipose tissue (VAT) in obese patients, which is correlated with increased tumor growth in an in vivo xenograft model. The increased tumor size is mechanistically associated with the activation of the PI3K/AKT/mTOR pathway, a downstream target of VEGF signaling, and its suppression decreased the growth-promoting effects of VAT on endometrial cancer cells. Similar to the human model systems, pathologic changes in endometrial cells in a hyperphagic obese mouse model are associated with increased body weight and hyperactive mTOR signaling. Analysis of human tissue specimens depicts increased in tumor vasculature and VEGF-mTOR activity in obese endometrial cancer patients compared with nonobese patients. Collectively, these results provide evidence that VEGF-mTOR signaling drives endometrial cell growth leading to hyperplasia and cancer.Implications: Adipocyte-derived VEGF–mTOR signaling may be an attractive therapeutic target against endometrial cancer in obese women. Mol Cancer Res; 16(2); 309–21. ©2017 AACR.

We probed the lifecycle of Epstein-Barr virus (EBV) on a cell-by-cell basis using single cell RNA sequencing (scRNA-seq) data from nine publicly available lymphoblastoid cell lines (LCLs). While the majority of LCLs comprised cells containing EBV in the latent phase, two other clusters of cells were clearly evident and were distinguished by distinct expression of host and viral genes. Notably, both were high expressors of EBV LMP1/BNLF2 and BZLF1 compared to another cluster that expressed neither gene. The two novel clusters differed from each other in their expression of EBV lytic genes, including glycoprotein gene GP350. The first cluster, comprising GP350

The diagnosis of endometrial atypical hyperplasia/endometrioid intraepithelial neoplasia (AH/EIN) remains challenging and subjective in some cases, with variable histologic criteria and differences of opinion among gynecologic pathologists, potentially leading to under/overtreatment. There has been growing interest in the use of specific immunohistochemical markers as adjuncts in AH/EIN diagnosis. For example, the World Health Organization 2020 Classification specifies that loss of Pten, Pax2, or mismatch repair proteins are desirable diagnostic criteria. Other markers, most notably β-catenin and Arid1a, are also aberrantly expressed in some AH/EIN. However, the performance of some markers individually-and more importantly as a group-has not been rigorously explored, raising questions as to which marker(s) or combination(s) is the most effective in practice. Formalin-fixed paraffin-embedded tissue sections from AH/EIN cases (n=111) were analyzed by immunohistochemistry for 6 markers: Pax2, Pten, Mlh1, β-catenin, Arid1a, and p53. Aberrant expression was tabulated for each case and marker. An additional set of normal endometria (n=79) was also analyzed to define optimal diagnostic criteria for marker aberrance. The performance characteristics of each marker, the entire panel, and subsets thereof were quantitatively and statistically analyzed. In order of number of cases detected, the most frequently aberrant markers in AH/EIN were Pax2 (81.1% of cases), Pten (50.5%), β-catenin (47.7%), Arid1a (7.2%), Mlh1 (4.5%), and p53 (2.7%). The majority of cases showed aberrant expression of ≥2 markers. All 6 markers together identified 92.8% of cases. Arid1a, Mlh1, and p53 were robust and readily scored markers, but all cases showing aberrant expression of these 3 markers were also detected by Pax2, Pten, or β-catenin. A focused panel of only 3 markers (Pax2, Pten, and β-catenin) showed optimal performance characteristics as a diagnostic adjunct in the histopathologic diagnosis of AH/EIN. Use of this panel is practicable and robust, with at least 1 of the 3 markers being aberrant in 92.8% of AH/EIN.

Endometrial polyps (EMPs) are common exophytic masses associated with abnormal uterine bleeding and infertility. Unlike normal endometrium, which is cyclically shed, EMPs persist over ovulatory cycles and after the menopause. Despite their usual classification as benign entities, EMPs are paradoxically associated with endometrial carcinomas of diverse histologic subtypes, which frequently arise within EMPs. The etiology and potential origins of EMPs as clonally-derived neoplasms are uncertain, but previous investigations suggested that EMPs are neoplasms of stromal origin driven by recurring chromosomal rearrangements. To better define benign EMPs at the molecular genetic level, we analyzed individual EMPs from 31 women who underwent hysterectomy for benign indications. The 31 EMPs were subjected to comprehensive genomic profiling by exome sequencing of a large panel of tumor-related genes including oncogenes, tumor suppressors, and chromosomal translocation partners. There were no recurring chromosomal rearrangements, and copy-number analyses did not reveal evidence of significant chromosome-level events. Surprisingly, there was a high incidence of single nucleotide variants corresponding to classic oncogenic drivers (i.e., definitive cancer drivers). The spectrum of known oncogenic driver events matched that of endometrial cancers more closely than any other common cancer. Further analyses including laser-capture microdissection showed that these mutations were present in the epithelial compartment at low allelic frequencies. These results establish a link between EMPs and the acquisition of endometrial cancer driver mutations. Based on these findings, we propose a model where the association between EMPs and endometrial cancer is explained by the age-related accumulation of endometrial cancer drivers in a protected environment that-unlike normal endometrium-is not subject to cyclical shedding.

The endometrium is unique as an accessible anatomic location that can be repeatedly biopsied and where diagnostic biopsies do not extirpate neoplastic lesions. We exploited these features to retrospectively characterize serial genomic alterations along the precancer/cancer continuum in individual women. Cases were selected based on (1) endometrial cancer diagnosis/hysterectomy and (2) preceding serial endometrial biopsies including for some patients an early biopsy before a precancer histologic diagnosis. A comprehensive panel was designed for endometrial cancer genes. Formalin‐fixed, paraffin‐embedded specimens for each cancer, preceding biopsies, and matched germline samples were subjected to barcoded high‐throughput sequencing to identify mutations and track their origin and allelic frequency progression. In total, 92 samples from 21 patients were analyzed, providing an opportunity for new insights into early endometrial cancer progression. Definitive invasive endometrial cancers exhibited expected mutational spectra, and canonical driver mutations were detectable in preceding biopsies. Notably, ≥1 cancer mutations were detected prior to the histopathologic diagnosis of an endometrial precancer in the majority of patients. In 18/21 cases, ≥1 mutations were confirmed by abnormal protein levels or subcellular localization by immunohistochemistry, confirming genomic data and providing unique views of histologic correlates. In 19 control endometria, mutation counts were lower, with a lack of canonical endometrial cancer hotspot mutations. Our study documents the existence of endometrial lesions that are histologically indistinct but are bona fide endometrial cancer precursors. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Cancer is instigated by mutator phenotypes, including deficient mismatch repair and p53-associated chromosomal instability. More recently, a distinct class of cancers was identified with unusually high mutational loads due to heterozygous amino acid substitutions (most commonly P286R) in the proofreading domain of DNA polymerase ε, the leading strand replicase encoded by POLE. Immunotherapy has revolutionized cancer treatment, but new model systems are needed to recapitulate high mutational burdens characterizing human cancers and permit study of mechanisms underlying clinical responses. Here, we show that activation of a conditional LSL-Pole(P286R) allele in endometrium is sufficient to elicit in all animals endometrial cancers closely resembling their human counterparts, including very high mutational burden. Diverse investigations uncovered potentially novel aspects of Pole-driven tumorigenesis, including secondary p53 mutations associated with tetraploidy, and cooperation with defective mismatch repair through inactivation of Msh2. Most significantly, there were robust antitumor immune responses with increased T cell infiltrates, accelerated tumor growth following T cell depletion, and unfailing clinical regression following immune checkpoint therapy. This model predicts that human POLE-driven cancers will prove consistently responsive to immune checkpoint blockade. Furthermore, this is a robust and efficient approach to recapitulate in mice the high mutational burdens and immune responses characterizing human cancers.

Significance Uterine carcinosarcoma (UCS) is an aggressive endometrial cancer variant distinguished from endometrial adenocarcinoma (EC) by admixed malignant epithelial and mesenchymal components (carcinoma and sarcoma). The molecular events underlying UCS are enigmatic, as cancer gene mutations are generally shared among UCS/EC. We take advantage of genetic approaches in mice to show that inactivation of Fbxw7 and Pten results in UCS through spontaneous acquisition of mutations in a third gene (Tp53), arguing for strong biological selection and synergism in UCS. We used this UCS model including tumor-derived cell lines to show that Fbxw7 loss drives epithelial–mesenchymal transition, explaining Fbxw7’s role in UCS. This model system argues that simultaneous genetic defects in 3 distinct pathways (Fbxw7, Pten/PI3K, Tp53) converge in UCS genesis., Uterine carcinosarcoma is an aggressive variant of endometrial carcinoma characterized by unusual histologic features including discrete malignant epithelial and mesenchymal components (carcinoma and sarcoma). Recent studies have confirmed a monoclonal origin, and comprehensive genomic characterizations have identified mutations such as Tp53 and Pten. However, the biological origins and specific combination of driver events underpinning uterine carcinosarcoma have remained mysterious. Here, we explored the role of the tumor suppressor Fbxw7 in endometrial cancer through defined genetic model systems. Inactivation of Fbxw7 and Pten resulted in the formation of precancerous lesions (endometrioid intraepithelial neoplasia) and well-differentiated endometrioid adenocarcinomas. Surprisingly, all adenocarcinomas eventually developed into definitive uterine carcinosarcomas with carcinomatous and sarcomatous elements including heterologous differentiation, yielding a faithful genetically engineered model of this cancer type. Genomic analysis showed that most tumors spontaneously acquired Trp53 mutations, pointing to a triad of pathways (p53, PI3K, and Fbxw7) as the critical combination underpinning uterine carcinosarcoma, and to Fbxw7 as a key driver of this enigmatic endometrial cancer type. Lineage tracing provided formal genetic proof that the uterine carcinosarcoma cell of origin is an endometrial epithelial cell that subsequently undergoes a prominent epithelial–mesenchymal transition underlying the attainment of a highly invasive phenotype specifically driven by Fbxw7.

Recently, the rates of contralateral prophylactic mastectomy (CPM) have increased significantly with no clear evidence of improvement in overall survival or breast cancer (BC) specific survival. In 2016, American Society of Breast Surgeons (ASBS) provided a consensus statement regarding when CPM should be-, can be- or may be offered and when it should be discouraged. In light of new recommendations, our study aimed to review factors that influenced the choice of CPM at our institution. Methods: This retrospective study was approved by the IRB. Patients who underwent CPM between January 2011 and May 2014 were included. Medical records were reviewed for documentation of risk factors that led to CPM. Patients were stratified into four categories based on the consensus statement. CPM “should be considered” included carriers of BRCA1/2 mutation, patients with strong FH (2 or more first degree relatives with BC) but not tested for BRCA and patients with history of mantle radiation; CPM “can be considered” included patients with intermediate FH (one first degree or multiple second/third degree relatives with BC), carriers of non-BRCA gene mutation, patients with prior history of BC and patients with strong FH but tested negative for BRCA; CPM “may be considered" included patients with psychological factors, those who denied adjuvant therapy and patients with multicentric disease in the index side. CPM “should be discouraged” included patients with advanced disease at the time of diagnosis, patients with weak FH (one second or third degree relative with BC) and patients with no significant FH or unknown FH. Results: Between January 2011 and May 2014, CPM was performed in 261 women ranging from 24 to 83 years (mean, 50 years). The number and percentage of women in each risk group is summarized in Table. Discussion: Based on the results, only 13% of the 261 women satisfied the criteria for when CPM "should be considered”, 38% for when CPM "can be or may be considered”, and in the remaining 49% CPM should have been discouraged. In light of the growing controversy regarding the overall benefit of CPM, it is important that the women with average-risk are well informed about the surgical risks vs. the benefits of CPM. Summary of the risks factors associated with contralateral prophylactic mastectomy (n=261)CPM should be considered for those at significant risk of CBC (total 13%) Carriers for BRCA 1/2 mutation2911.1%Strong Family history (patient not tested for BRCA)20.8%History of mantle radiation31.1%CPM can be considered for those at lower risk of CBC (total 30.6%) Intermediate family history6023%Carriers for non-BRCA gene mutation31.1%History of prior breast carcinoma135%Strong Family history, BRCA negative41.5%CPM may be considered for other reasons (total 7.6%) Psychological factors62.3%Patient denied adjuvant chemo or radiation therapy31.1%Multicentric disease in the index breast114.2%CPM should be discouraged (48.8%) Advanced disease at diagnosis41.5%Weak family history7829.8%No family history4115.6%Unknown family history, no other significant personal history51.9%CPM: contralateral prophylactic mastectomy; CBC: contralateral breast cancer Citation Format: Drobysheva A, Butt Y, Sahoo S. Assessment of risk factors in women undergoing contralateral prophylactic mastectomy after breast cancer diagnosis: Experience at an academic medical center [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-22-14.

// Subhransu S. Sahoo 1 , Min Yuan Quah 2 , Sarah Nielsen 3 , Joshua Atkins 4 , Gough G. Au 2 , Murray J. Cairns 4 , Pravin Nahar 5 , Janine M. Lombard 6 and Pradeep S. Tanwar 1 1 Gynaecology Oncology Group, School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, New South Wales, Australia 2 The Picornaviral Research Unit, School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, New South Wales, Australia 3 Hunter Cancer Biobank, University of Newcastle, Callaghan, New South Wales, Australia 4 Discipline of Pharmacy and Experimental Pharmacology, School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, New South Wales, Australia 5 Department of Maternity and Gynaecology, John Hunter Hospital, New Lambton Heights, New South Wales, Australia 6 Department of Medical Oncology, Calvary Mater Newcastle, Waratah, New South Wales, Australia Correspondence to: Pradeep S. Tanwar, email: // Keywords : microenvironment, ECM, endometrial cancer, TGF-β signalling, metastasis Received : May 05, 2017 Accepted : May 07, 2017 Published : May 22, 2017 Abstract Although aggressive invasion and distant metastases are an important cause of morbidity and mortality in patients with endometrial cancer (EC), the requisite events determining this propensity are currently unknown. Using organotypic three-dimensional culture of endometrial cancer cell lines, we demonstrated anti-correlated TGF-β signalling gene expression patterns that arise among extracellular matrix (ECM)-attached cells. TGF-β pathway seemed to be active in EC cells forming non-glandular colonies in 3D-matrix but weaker in glandular colonies. Functionally we found that out of several ECM proteins, fibronectin relatively promotes Smad phosphorylation suggesting a potential role in regulating TGF-β signalling in non-glandular colonies. Importantly, alteration of TGF-β pathway induced EMT and MET in both type of colonies through slug protein. The results exemplify a crucial role of TGF-β pathway during EC metastasis in human patients and inhibition of the pathway in a murine model impaired tumour cell invasion and metastasis depicting an attractive target for therapeutic intervention of malignant tumour progression. These findings provide key insights into the role of ECM-derived TGF-β signalling to promote endometrial cancer metastasis and offer an avenue for therapeutic targeting of microenvironment derived signals along with tumour cells.

Chikungunya virus (CHIKV), a virus that induces pathogenic inflammatory host immune responses, is re-emerging worldwide, and there are currently no established antiviral control measures. Transient receptor potential vanilloid 1 (TRPV1), a non-selective Ca

Epithelial and stromal communications are essential for normal uterine functions and their dysregulation contributes to the pathogenesis of many diseases including infertility, endometriosis, and cancer. Although many studies have highlighted the advantages of culturing cells in 3D compared to the conventional 2D culture system, one of the major limitations of these systems is the lack of incorporation of cells from non-epithelial lineages. In an effort to develop a culture system incorporating both stromal and epithelial cells, 3D endometrial cancer spheroids are developed by co-culturing endometrial stromal cells with cancerous epithelial cells. The spheroids developed by this method are phenotypically comparable to in vivo endometrial cancer tissue. Proteomic analysis of the co-culture spheroids comparable to human endometrial tissue revealed 591 common proteins and canonical pathways that are closely related to endometrium biology. To determine the feasibility of using this model for drug screening, the efficacy of tamoxifen and everolimus is tested. In summary, a unique 3D model system of human endometrial cancer is developed that will serve as the foundation for the further development of 3D culture systems incorporating different cell types of the human uterus for deciphering the contributions of non-epithelial cells present in cancer microenvironment.

Ovarian cancer is a disease of older women. However, the molecular mechanisms of ovarian aging and their contribution to the pathogenesis of ovarian cancer are currently unclear. mTOR signalling is a major regulator of aging as suppression of this pathway extends lifespan in model organisms. Overactive mTOR signalling is present in up to 80% of ovarian cancer samples and is associated with poor prognosis. This study examined the role of mTOR signalling in age-associated changes in ovarian surface epithelium (OSE). Histological examination of ovaries from both aged mice and women revealed OSE cell hyperplasia, papillary growth and inclusion cysts. These pathological lesions expressed bonafide markers of ovarian cancer precursor lesions, Pax8 and Stathmin 1, and were presented with elevated mTOR signalling. To understand whether overactive mTOR signalling is responsible for the development of these pathological changes, we analysed ovaries of the Pten trangenic mice and found significant reduction in OSE lesions compared to controls. Furthermore, pharmacological suppression of mTOR signalling significantly decreased OSE hyperplasia in aged mice. Treatment with mTOR inhibitors reduced human ovarian cancer cell viability, proliferation and colony forming ability. Collectively, we have established the role of mTOR signalling in age-related OSE pathologies and initiation of ovarian cancer.

Background: Testing of biomarkers in biopsies is a critical driver of determining therapy in patients diagnosed with invasive breast cancer. In the past, open surgical biopsy was considered to be the gold standard, but has been supplanted by the less invasive core needle biopsy. It is therefore imperative to know if such biopsies are representative of disease existing within the entirety of the tumor. This is especially the case now that neoadjuvant therapy is offered to patients with early stage tumor prior to surgical excision. In order to confirm that core biopsies are sufficient to serve as the launch point for treatment decision, we have conducted a retrospective review to compare the biomarker results of core biopsies with their corresponding excisional specimens. Previous studies have contained a smaller sample size, thus this is the largest single-site study of its kind. Methods: Data from patients with invasive breast cancer diagnosed between 2006 and 2013 have been retrospectively studied. Results for estrogen receptor (ER), progesterone receptor (PR) and Her2 status were analyzed. When the core biopsy and excisional specimens are either both "positive" or both "negative," the pair is considered to be "concordant." Otherwise, the pair is categorized as "discordant." As per the current ASCO/CAP guideline, hormone receptor status (estrogen and progesterone receptors) is considered positive if there were at least 1% tumor cells positive for either ER or PR. Both IHC and FISH concordance are evaluated for Her2 status. Patients who received neoadjuvant therapy of any kind were excluded from this study. Results: A total of 571 pairs of data totaling 1142 samples were analyzed in this study. Concordance for ER status is 97%, and for PR status is 92%. Concordance for hormone receptor status (when results of ER and PR are combined) between core biopsy and excision is 99%. Concordance for Her2 status, using FISH as the gold standard is 99%. Discussion: Typically, tumors that are ER+ are often also PR+. Nevertheless, they are often treated the same with hormonal therapy whether ER+PR+, ER+PR-, or, less commonly, ER-PR+. Almost all laboratories perform both ER and PR as a standard testing protocol for all breast carcinomas. Therefore, the lower concordance rate for only PR status without taking into consideration ER result is less meaningful. This study shows very high concordance rates for hormone receptor and Her2 status between core needle biopsy and excisional specimens, reiterating that treatment of invasive breast cancers based on the marker results obtained from core needle biopsies is appropriate. Citation Format: Music J, Sahoo S. Correlation of predictive markers in invasive breast carcinoma in core and excision specimens: A retrospective review. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-08-35.

Cancer is characterized by increased mutation rate, and recent work has led to a deeper understanding of mutator phenotypes and underlying molecular mechanisms. Differences in the mutational landscape of individual cancers underlie key aspects of clinical behavior. For example, overall base substitution rate is the best predictor of immune therapy response. Most genetically engineered mouse models of cancer (GEMMs) reiterate a few driver events but fail to recapitulate the high mutational loads that are the ultimate cause of most human cancer, making GEMMs inadequate for many aspects of tumor behavior, such as immune responses. The highest base substitution rates in cancers (≥100/Mb) result from specific heterozygous single amino acid substitutions (usually P286R) in the proofreading domain of DNA polymerase epsilon (POLE), rendering POLE highly error prone. POLE mutations are most common in endometrial cancer but occur with lower incidence in a wide range of cancers. We hypothesized that GEMMs could be generated by recapitulating PoleP286R via conditional knockin. Previously, we showed that constitutive expression of PoleP286R throughout the body triggered malignancies of diverse lineages. Mice harboring LSL-PoleP286R and the endometrial BAC-Sprr2f-Cre developed endometrial cancers starting at 1 year. Endometrial cancers exhibited histologic features previously reported in human POLE tumors, and metastasized in all mice (p This abstract is also being presented as Poster A34. Citation Format: Hao-Dong Li, Changzheng Lu, He Zhang, Ileana C. Cuevas, Subhransu S. Sahoo, Yang-Xin Fu, Diego H. Castrillon. Polymerase-mediated ultramutagenesis: A new approach for modeling the high mutational load of human cancer [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr PR13.

Endometrial cancer (EC) is one of the most frequently diagnosed cancers in women, and despite recent therapeutic advances, in many cases, treatment failure results in cancer recurrence, metastasis, and death. Current research demonstrates that the interactive crosstalk between two discrete cell types (tumor and stroma) promotes tumor growth and investigations have uncovered the dual role of the stromal cells in the normal and cancerous state. In contrast to tumor cells, stromal cells within the tumor microenvironment (TME) are genetically stable. However, tumor cells modify adjacent stromal cells in the TME. The alteration in signaling cascades of TME from anti-tumorigenic to pro-tumorigenic enhances metastatic potential and/or confers therapeutic resistance. Therefore, the TME is a fertile ground for the development of novel therapies. Furthermore, disrupting cancer-promoting signals from the TME or re-educating stromal cells may be an effective strategy to impair metastatic progression. Here, we review the paradoxical role of different non-neoplastic stromal cells during specific stages of EC progression. We also suggest that the inhibition of microenvironment-derived signals may suppress metastatic EC progression and offer novel potential therapeutic interventions.

Obesity is responsible for increased morbidity and mortality in endometrial cancer. Despite the positive correlation of body mass index (BMI) or obesity in endometrial carcinogenesis, the contribution of adipose tissue to the pathogenesis of endometrial hyperplasia and cancer is unclear. This study clarifies the role of adipocytes in the pathogenesis of endometrial cancer by demonstrating that adipocyte-conditioned medium (ACM) increases proliferation, migration, and survival of endometrial cancer cells compared with preadipocyte-conditioned medium (PACM). Comparative cytokine array analysis of ACM and PACM reveal upregulation of a group of cytokines belonging to the VEGF signaling pathway in ACM. VEGF protein expression is upregulated in visceral adipose tissue (VAT) in obese patients, which is correlated with increased tumor growth in an in vivo xenograft model. The increased tumor size is mechanistically associated with the activation of the PI3K/AKT/mTOR pathway, a downstream target of VEGF signaling, and its suppression decreased the growth-promoting effects of VAT on endometrial cancer cells. Similar to the human model systems, pathologic changes in endometrial cells in a hyperphagic obese mouse model are associated with increased body weight and hyperactive mTOR signaling. Analysis of human tissue specimens depicts increased in tumor vasculature and VEGF-mTOR activity in obese endometrial cancer patients compared with nonobese patients. Collectively, these results provide evidence that VEGF-mTOR signaling drives endometrial cell growth leading to hyperplasia and cancer. Implications: Adipocyte-derived VEGF–mTOR signaling may be an attractive therapeutic target against endometrial cancer in obese women. Mol Cancer Res; 16(2); 309–21. ©2017 AACR.