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Background: Estimated lifetime ovulatory years (LOY) is the difference between ages at menopause and menarche subtracting time for events interrupting ovulation. We tested whether LOY influence sex-hormone levels in postmenopausal women not using hormone therapy. Methods: Hormones, including estradiol and testosterone, were measured in 1976 postmenopausal women from the Nurses’ Health Study in plasma collected in 1990. Effects of age, years since menopause, body mass index (BMI), smoking status, and hysterectomy on hormone levels were assessed by t-tests and ANOVA. Multivariable linear regression was used to assess associations between LOY and hormones adjusted for potential confounders and the trend in hormone levels per 5-year increases in LOY estimated. Results: Women in the sample averaged: 61.4 years old at blood draw, 11.0 years since menopause, with a BMI of 25.8 kg/m2. 17.5% had a hysterectomy and 13.8% were current smokers. These characteristics were associated with one or more hormone levels and included as adjustment variables. Each 5-year increase in LOY was associated with a 6.0% increase in testosterone (95% CI 3.3%, 8.7%) in all women. In women with above-average BMI, each 5-year increase in LOY was associated with a 7.3% (3.5%, 11.2%) increase in testosterone, a 6.9% (2.7%,11.3%) increase in estradiol, and a 6.9% (2.9%,10.9%) increase in estrone. Conclusion: Greater LOY is associated with higher testosterone in postmenopausal women as well as greater estradiol in those with above-average BMI. This may be due to an accumulation of functioning stromal and thecal cells from repeated ovulation and peripheral conversion of testosterone. Citation Format: Daniel W. Cramer, Allison F. Vitonis, Tianyi Huang, Amy L. Shafrir, Heather Eliassen, Robert L. Barbieri, Susan E. Hankinson. Ovulatory years prior to menopause and postmenopausal endogenous hormone levels [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB137.

Background: Ovarian cancer is a deadly gynecologic cancer, accounting for approximately 14,000 deaths in the US annually. Lack of early detection modalities leads to advanced stage diagnosis with poorer prognosis. Cancer antigen 125 (CA125) is the most promising single biomarker for ovarian cancer screening. However, two large randomized screening trials comparing the combination of CA125 and transvaginal ultrasound to usual care did not show significant improvement in overall survival. Here, we examined whether using predicted personal CA125 cutpoints based on individual characteristics in postmenopausal women would improve discrimination of epithelial ovarian cancer cases from controls better than using a fixed cutpoint of 35 U/mL. Method: We first determined the effect estimates needed to calculate the predicted 90th and 95th percentile cutpoint of blood CA125 values for each individual using quantile regression model including validated predictors of CA125 (i.e. age, race, body-mass index, smoking status, parity, hysterectomy, age at last menstrual period, and duration of hormone therapy) using data on 28,998 women without ovarian cancer from Prostate Lung Colon and Ovarian Cancer Screening study (PLCO), European Prospective Investigation into Nutrition and Cancer (EPIC), Nurses' Health Studies (NHS/NHSII), and the New England Case Control Study. Then, we examined whether personalized cutpoints performed better than the fixed cutpoint of 35 U/mL in discriminating ovarian cancer cases from controls overall and by time between blood draw to clinical diagnosis using data on 581 incident ovarian cancer cases with CA125 measured up to 24 months prior to clinical diagnosis and 28,226 controls from PLCO, EPIC, and NHS/NHSII. Results: We observed that use of personalized CA125 cutpoints showed improved reclassification of ovarian cancer cases and controls compared to using the fixed cutpoint of 35 U/mL in blood CA125 measured 6 to 12 months prior to diagnosis with net reclassification improvement of 15% using the 90th percentile cutpoint and 12% using the 95th percentile cutpoint. The net reclassification improvement decreased as time between blood draw to clinical diagnosis increased. Conclusion: Our results suggest that redefining the upper limit of normal CA125 values using personalized cutpoints has the potential to modestly improve the performance of CA125 in ovarian cancer screening among average risk postmenopausal women. Citation Format: Naoko Sasamoto, Bernard A. Rosner, Renée T. Fortner, Britton Trabert, Allison F. Vitonis, Stephanie Nartey, Raina N. Fichorova, Linda J. Titus, Daniel W. Cramer, Nicolas Wentzensen, Shelley S. Tworoger, Rudolf Kaaks, Kathryn L. Terry. Personalized cutpoints of CA125 to improve early detection of ovarian cancer in postmenopausal women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 888.

Introduction: In pediatric cancer, there is an urgent need for research that can identify and validate new therapeutic modalities for pediatric cancers. Diagnostic biopsy samples remain the ideal tissue samples for research and must be collected from surplus biopsy material, which is often extremely limited. Here we describe our efforts to optimize tissue allocation for clinical care and research as a joint effort between Department of Pathology at Boston Children’s Hospital and the Pediatric Solid Tumor Program at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. Methods: Oncologists, pathologists, surgeons, interventional radiologists, pathology technical staff, and clinical research coordinators participated in the workflow design. The group agreed to develop a formalized procedure to address these five steps: 1) patient identification and consent, 2) prioritization of research objectives, 3) advance communication of tissue requests to the pathology staff, 4) tissue preparation, and 5) tissue distribution. It was unanimously agreed that all tissue must flow through the pathology department. On or before the day of surgery, clinical research teams sent the pathologist a patient-specific electronic communication indicating research consent and detailing the prioritized disease-specific research requests, including the procedure planned, all tissue types and tissue volumes requested, and details of any special preparation needed, such as avoiding decalcification in bone tumors. The communication was optimized to be clear but brief, with the goal of minimizing the impact to the pathologist’s work load. Pathologists were surveyed about the change in process. Results: Over a five-year period (2013-2018), 662 pediatric DFCI/BCH solid tumor patients have consented to one or more trials that request FFPE, frozen, or fresh tissue. Tumor types represent a spectrum of cases, with many rare and singular diagnoses. Of 1,768 research tissue requests, 1,121 (63%) were fulfilled. Clinical study requests from resection specimens were the most likely to be fulfilled (95% of 390 requests fulfilled), while basic research requests from core biopsies were the least likely to be fulfilled (26% of 255 requests fulfilled). In an anonymous survey, 7 of 7 pathologists report that the process had improved since the introduction of the electronic communication. Conclusions: A collaborative and informed model for tissue allocation is successful in distributing tissue for clinical studies and basic research projects. Our workflows and policies have gained pathologist approval and streamlined our processes. As clinical and research programs evolve, a thoughtful tissue allocation process will facilitate ongoing research. Citation Format: R. Seth Pinches, Catherine Clinton, Abigail Ward, Stephanie C Meyer, Alyaa Al-Ibraheemi, Suzanne Forrest, Gianna R. Strand, Hillary Detert, Anne Piche-Schulman, Kristen Gil, Tamara Restrepo, Rosemarie Tavares-Proulx, Jeffrey Goldsmith, Raja Shaikh, Christopher Weldon, Sanda Alexandrescu, Allison F. O’Neill, Monica Hollowell, Marian H. Harris, Katherine A. Janeway, Brian D. Crompton, Alanna Church. Improving tissue allocation for research in pediatric solid tumors [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A67.

BACKGROUND: TP53 mutations are rare across pediatric cancers. Recent work using CRISPR-Cas9 screens has demonstrated that MDM2 and MDMX are strong dependencies in a range of TP53-wildtype pediatric malignancies. Increased expression of MDM2 and MDMX is a common mechanism for suppressing p53 in pediatric malignancies and can occur by copy number gain or amplification, as has been reported in retinoblastoma and hepatoblastoma. In pediatric high-grade gliomas, activating PPM1D mutations drive p53 suppression, likely through MDM2 stabilization. ALRN-6924 is a novel, first-in-class, cell-permeating stapled peptide that disrupts the inhibitory interactions between MDM2/MDMX(MDM4) and p53. ALRN-6924 has been evaluated in two adult Phase I trials, with good tolerability and evidence of clinical activity across a range of cancer subtypes. Given the oncogenic roles of MDM2 and MDMX in pediatric malignancies, we developed a Phase I clinical trial designed to evaluate the tolerability, pharmacokinetics, and pharmacodynamic and antitumor activity of ALRN-6924. METHODS: This is a Phase I, open-label, investigator-initiated multicenter study of ALRN-6924 in children 1-21 years of age with relapsed/refractory cancer (NCT03654716). The primary objectives are to determine the recommended phase 2 dose, and to describe toxicities and pharmacokinetic parameters of ALRN-6924 in this population. The monotherapy arm consists of two cohorts: Cohort A for patients with TP53-wildtype solid tumors and lymphomas; and Cohort B for patients with retinoblastoma, or TP53-wildtype tumors that meet any of the following criteria: hepatoblastoma, malignant rhabdoid tumor, MDM2 or MDMX amplification, TET2 loss, or PPM1D activating mutations. Patients with CNS primary tumors are only eligible for Cohort B. In Cohorts A and B, patients receive ALRN-6924 intravenously on Days 1, 4, 8 and 11 of a 21-day cycle starting at a dose of 2.2 mg/kg. An expansion cohort for patients eligible for Cohort B will open following completion of monotherapy dose escalation. Patients with relapsed/refractory leukemias enroll to Cohort C and receive ALRN-6924 in combination with low-dose cytarabine on days 1, 8 and 15 of a 28-day cycle starting at a dose of 2.7 mg/kg. Pharmacokinetic sampling and pharmacodynamic testing (serum MIC-1 modulation) is required for all patients. Correlative biology studies will include evaluation of circulating tumor DNA for TP53 mutations in patients with solid tumors and serial assessment of leukemic blasts in patients with relapsed leukemia. Enrollment began in October 2018. Up to 69 patients will be enrolled. Citation Format: David S. Shulman, Kieuhoa T. Vo, Elizabeth Fox, Jodi A. Muscal, Loren D. Walensky, Yana Pikman, Kimberly Stegmaier, Alanna Church, Brian D. Crompton, Andrew E. Place, Susan N. Chi, Allison F. O'Neill, Junne Kamihara, Suzanne Ezrre, Cecilia Carlowicz, Dawn Pinchasik, Hasan Al-Sayegh, Clement Ma, Wendy B. London, Steven G. DuBois. A Phase I multicenter trial of the dual MDM2/MDMX inhibitor ALRN-6924 in children and young adults with relapsed/refractory pediatric cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT112.

Aberrant cell-cycle progression is a hallmark feature of cancer cells. Cyclin-dependent kinases 4 and 6 (CDK4/6) drive progression through the G1 stage of the cell cycle, at least in part, by inactivating the tumor suppressor, retinoblastoma. CDK4/6 are targetable and the selective CDK4/6 inhibitor, palbociclib, was recently FDA approved for the treatment of estrogen receptor–positive, HER2-negative advanced breast cancer. In cutaneous melanoma, driver mutations in NRAS and BRAF promote CDK4/6 activation, suggesting that inhibitors such as palbociclib are likely to provide therapeutic benefit in combination with BRAF inhibitors and/or MEK inhibitors that are FDA-approved. However, the determinants of the response to CDK4/6 inhibitors alone and in combination with other targeted inhibitors are poorly defined. Furthermore, in vivo systems to quantitatively and temporally measure the efficacy of CDK4/6 inhibitors and determine the extent that CDK activity is reactivated during acquired resistance are lacking. Here, we describe the heterogeneous effects of CDK4/6 inhibitors, the expression of antiapoptotic proteins that associate with response to CDK4/6 and MEK inhibitors, and the development of a luciferase-based reporter system to determine the effects of CDK4/6 inhibitors alone and in combination with MEK inhibitors in melanoma xenografts. These findings are likely to inform on-going and future clinical trials utilizing CDK4/6 inhibitors in cutaneous melanoma. Cancer Res; 76(18); 5455–66. ©2016 AACR.

Background: Cancer antigen 125 (CA125) is a membrane-bound glycosylated mucin that has been reported to be the most promising biomarker for ovarian cancer screening, although results from two large randomized trials comparing screening using CA125 and transvaginal ultrasound to usual care have shown no clinically significant difference in ovarian cancer mortality. A major limitation of CA125 as an ovarian cancer screening biomarker has been low specificity and variation between individuals by personal characteristics. Identifying personal characteristics that influence CA125 levels could be used to create personalized thresholds for CA125 for each individual, thereby improving its performance as an ovarian cancer screening biomarker. However, reports on factors that influence CA125 among premenopausal women are limited. Methods: We evaluated the association between reproductive and lifestyle factors and CA125 among 828 premenopausal population-based controls enrolled in the New England Case-Control study between 1992 and 2008. CA125 was measured using the CA125II assay at the CERLab at Boston Children's Hospital. We developed a prediction model of log-transformed CA125 using stepwise linear regression with Results: In our univariate analyses, older age and endometriosis were associated with significantly higher CA125 while tubal ligation, hysterectomy, and time since last menstrual period were associated with significantly lower CA125 (p Conclusion: Efforts to validate this CA125 prediction model in an independent cohort of premenopausal women and evaluate whether using the personalized CA125 cutoff based on this prediction model discriminates cases and controls better than the single 35 cutoff are ongoing. Citation Format: Naoko Sasamoto, Ana Babic, Bernard A. Rosner, Allison F. Vitonis, Daniel W. Cramer, Shelley S. Tworoger, Kathryn L. Terry. Prediction model of CA125 among premenopausal women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2205.

We recently identified the immunoglobulin-CAM CD155/PVR (the poliovirus receptor) as a regulator of cancer invasiveness and glioma migration, but the mechanism through which CD155/PVR controls these processes is unknown. Here, we show that expression of CD155/PVR in rat glioma cells that normally lack this protein enhances their dispersal both in vitro and on primary brain tissue. CD155/PVR expression also reduced substrate adhesion, cell spreading, focal adhesion density, and the number of actin stress fibers in a substrate-dependent manner. Furthermore, we found that expression of CD155/PVR increased Src/focal adhesion kinase signaling in a substrate-dependent manner, enhancing the adhesion-induced activation of paxillin and p130Cas in cells adhering to vitronectin. Conversely, depletion of endogenous CD155/PVR from human glioma cells inhibited their migration, increased cell spreading, and down-regulated the same signaling pathway. These findings implicate CD155/PVR as a regulator of adhesion signaling and suggest a pathway through which glioma and other cancer cells may acquire a dispersive phenotype.

Hypoxia within solid tumors decreases therapeutic efficacy, and identification of hypoxia markers may influence the choice of therapeutic modality. Here, we used a proteomic approach to identify hypoxia-regulated proteins and validated their use as endogenous indicators of tumor hypoxia. Using two-dimensional gel electrophoresis and PowerBlot (antibody-based array), we identified a group of 20 proteins that are increased ≥1.5-fold during hypoxia. The majority of these proteins such as IκB kinase β (IKKβ), MKK3b, highly expressed in cancer (HEC), density-regulated protein 1, P150glued, nuclear transport factor 2, binder of ARL 2, Paxillin, and transcription termination factor I have not been previously reported to be hypoxia inducible. The increase in these proteins under hypoxia was mediated through posttranscriptional mechanisms. We additionally characterized the role of IKKβ, a regulator of the nuclear factor-κB transcription factor, during hypoxia. We demonstrated that IKKβ mediates cell survival during hypoxia and is induced in a variety of squamous cell carcinoma cell lines. Furthermore, we showed that IKKβ expression from tumor specimens correlated with tumor oxygenation in patients with head and neck squamous cell carcinomas. These data suggest that IKKβ is a novel endogenous marker of tumor hypoxia and may represent a new target for anticancer therapy.

Increased polyamine synthesis and inflammation have long been associated with intraepithelial neoplasia and their progression to malignant tumor growth, including lung cancer. Targeting multiple pathways simultaneously with low-dose combinations may be an effective approach to modulate different pathways and their downstream signaling, which may result in an increased efficacy and reduced side effects than a single-agent high dose strategy. The aim of the present study was to investigate the effects of DFMO (ODC inhibitor) and licofelone, a dual 5-LOX-COX inhibitor, individually and in combination, on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone NNK-induced lung adenoma and progression to adenocarcinoma in female A/J mice. At 6 weeks of age, mice (25 /group) were fed AIN-76A-modified diet, and one week later, lung tumors were induced with a single intraperitoneal (i.p.) injection of 10 μmol NNK/mouse. Three weeks after the NNK treatment, groups of mice were fed with either control or experimental diets containing DFMO (1500 or 3000 ppm) or Licofelone (200 or 400 ppm) or combination of low doses of DFMO and Licofelone. Mice were killed after 17 or 34 weeks of drug exposure and tumors were evaluated via histopathology and lung tumors were assayed for modification of various biomarkers of proliferation and apoptosis. Results suggest that both DFMO and licofelone showed dose-dependent inhibition of NNK-induced lung adenoma progression to adenocarcinoma. At high dose DFMO and Licofelone showed 46% and 55% of adenocarcinoma inhibition. Importantly, low dose combination of DFMO and licofelone showed more pronounced effects at both 17 or 34 weeks in inhibiting the total adenocarcinomas (adenoma and adenocarcinoma progression) by >65% and somewhat in a synergistic manner as compared to individual low doses of DFMO and licofelone. Combination-treated lung tumors exhibited modulation of ODC pathway key components (Arg1, Oat, Oaz, SRM, SMS, and SAT) along with decreased proliferation (PCNA, cyclin D1 and Cyclin A) and increased expression of p53, p21 and p27 compared to tumors from mice fed with control diet. These data suggest that targeting ODC plus 5-LOX/COX decreases the progression of adenoma to adenocarcinoma. Furthermore, adenoma progression delay by combination of DFMO and Licofelone is associated with decreased tumor invasive markers such as MMTPs and EMT markers. In conclusion, targeting two or more pathways is an effective chemopreventive approach for high-risk lung cancer individual's particularly former tobacco smokers with lung hyperplasia and adenomas. (Supported by Kerley-Cade Chair Endowment and NCI-N01-CN-53300) Citation Format: Gaurav Kumar, Jagan Mohan R. Patolla, Venkateshwar Madka, Altaf Mohammed, Li Qian, Yuting Zhang, Laura Biddick, Anil Singh, Allison Gillaspy, Stanley Lightfoot, Levy Kopelovich, Vernon E. Steele, Chinthalapally V. Rao. Simultaneous targeting of ODC and 5-LOX/COX block the tobacco carcinogen-induced lung adenoma progression to adenocarcinoma in A/J mice. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2625.

Aberrant cell cycle progression is a hallmark feature of cancer cells. Cyclin-dependent kinase 4 and 6 (CDK4/6) drive progression through the G1 stage of the cell cycle, at least in part, by inactivating the tumor suppressor, retinoblastoma (RB). CDK4/6 are targetable and the selective CDK4/6 inhibitor, palbociclib (IBRANCE/PD-0332991), was recently FDA approved for the treatment of estrogen receptor-positive, HER2-negative advanced breast cancer. In cutaneous melanoma, driver mutations in NRAS and BRAF signal to promote CDK4/6 activation suggesting that inhibitors such as palbociclib are likely to provide therapeutic benefit most likely in combination with BRAF and/or MEK inhibitors that are FDA-approved. However, the determinants of the response to CDK4/6 inhibitors alone and in combination with other targeted inhibitors are poorly defined. Furthermore, in vivo systems to quantitatively and temporally measure the efficacy of CDK4/6 inhibitors and determine the extent that CDK activity is reactivated during acquired resistance are lacking. Here, we describe the heterogeneous effects of CDK4/6 inhibitors, the expression of anti-apoptotic proteins that associate with response to CDK4/6 and MEK inhibitors, and the development of a luciferase-based reporter system to determine the effects of CDK4/6 inhibitors alone and in combination with MEK inhibitors in melanoma xenografts. These findings are likely to inform on-going and future clinical trials utilizing CDK4/6 inhibitors in cutaneous melanoma. Citation Format: Jessica L. Teh, Timothy Purwin, Evan J. Greenawalt, Inna Chervoneva, Allison Goldberg, Michael E. Davies, Andrew Aplin. An in vivo reporter to quantitatively and temporally analyze the effects of CDK4/6 inhibitor-based therapies in melanoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5199.

Among the proinflammatory mediators, platelet-activating factor (PAF, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphorylcholine) is a major primary and secondary messenger involved in intracellular and extracellular communication. Evidence suggests that PAF plays a significant role in oncogenic transformation, tumor growth, angiogenesis, and metastasis. However, PAF, with its receptor (PAFR) and their downstream signaling targets, has not been thoroughly studied in cancer. Here, we characterized the PAFR expression pattern in 4 normal human ovarian surface epithelial (HOSE) cell lines, 13 ovarian cancer cell lines, paraffin blocks (n = 84), and tissue microarrays (n = 230) from patients with ovarian cancer. Overexpression of PAFR was found in most nonmucinous types of ovarian cancer but not in HOSE and mucinous cancer cells. Correspondingly, PAF significantly induced cell proliferation and invasion only in PAFR-positive cells (i.e., OVCA429 and OVCA432), but not in PAFR-negative ovarian cells (HOSE and mucinous RMUG-L). The dependency of cell proliferation and invasion on PAFR was further confirmed using PAFR-specific small interfering RNA gene silencing probes, antibodies against PAFR and PAFR antagonist, ginkgolide B. Using quantitative multiplex phospho-antibody array technology, we found that tyrosine phosphorylation of EGFR/Src/FAK/paxilin was coordinately activated by PAF treatment, which was correlated with the activation of phosphatidylinositol 3-kinase and cyclin D1 as markers for cell proliferation, as well as matrix metalloproteinase 2 and 9 for invasion. Specific tyrosine Src inhibitor (PP2) reversibly blocked PAF-activated cancer cell proliferation and invasion. We suggest that PAFR is an essential upstream target of Src and other signal pathways to control the PAF-mediated cancer progression. [Cancer Res 2008;68(14):5839–48]

Introduction: Hepatocellular Carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide. Chronic viral hepatitis, non-alcoholic steatohepatitis and cirrhosis are considered to be major risk factors for the development of HCC. The risk of HCC increases significantly in patients with chronic hepatitis C virus (HCV) infection and metabolic diseases. Thus, HCC represents a wide-ranging public health issue worldwide. Our recent studies have revealed a positive correlation between expression of the tumor stem cell (TSC) marker, doublecortin-like kinase (DCLK1) and cancer growth in liver, colon and pancreas. However, the molecular mechanism by which its overexpression impacts key signaling pathways during hepatocarcinogenesis is largely unknown. We have previously shown a dynamic relationship between active HCV replication and expression of a few TSC markers including DCLK1. Our published reports further suggest that DCLK1 positively affects the viral replication and transcription factors that promote epithelial-mesenchymal transition. These observations prompted us to investigate a possible DCLK1-controlled signaling network in HCC. Methods: We used transcriptome analysis of DCLK1-overexpressing and HCV replicon co-expressing cell lines, RNA interference, Huh7 hepatoma cells-derived tumor xenografts, patient's liver tissues and normal human hepatocytes-derived hepatospheroids to investigate DCLK1-regulated signaling pathways in the liver. Immunohistochemical staining, real-time PCR and Western blot were used to validate our observations. The siRNAs and shRNAs against DCLK1 were used to monitor inhibition of cell migration and tumor growth. Results: Although normal human liver lacks detectable DCLK1, extensive DCLK1 expression was observed in lymphoid aggregates, epithelial and stromal cells, lymphocytes, and bile ducts in HCV-positive patients with cirrhosis and HCC. The DCLK1 expression correlated with pro-inflammatory S100A9 levels and activation of NFκB. Normal human hepatocytes-derived spheroids acquired DCLK1 expression, and differentiated into stem/progenitor-like and neuron-like cells upon stimulation with serum. Silencing of DCLK1 inhibited S100A9 expression and hepatoma cell migration. Based on transcriptome data and validation at protein levels, we found a novel DCLK1-controlled feed-forward-like signaling network that potentially drives inflammation and tumorigenesis in the liver. DCLK1 was also found to regulate SMARCA2 (hBRM) protein that participates in the formation of tumor-associated SW1/SNF1 chromatin remodeling complexes. Conclusions: The TCS marker, DCLK1, appears to be a master regulator of inflammatory, oncogenic and chromatic remodeling networks. It is possible to target this signal regulator for preventing hepatic inflammation and liver neoplasia. Citation Format: Naushad Ali, Parthasarathy Chandrakesan, Charles B. Nguyen, Sanam Husain, Allison F. Gillaspy, Mark Huycke, William L. Berry, Randal May, Dongfeng Qu, Nathaniel Weygant, Sripathi M. Sureban, Danny N. Dhanasekaran, Courtney W. Houchen. The tumor stem cell marker doublecortin-like kinase (DCLK1) activates inflammatory and carcinogenic signals in hepatocellular carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2239. doi:10.1158/1538-7445.AM2015-2239

Galectins, a family of glycan-binding proteins, interact with cell-surface glycoconjugates and influence tumor progression by triggering a cascade of transmembrane signaling events which influence pathogenesis of cancer or tumor outcome. Despite considerable progress in identifying the involvement of individual galectins in tumor biology, an integrated portrait of the galectin network in different organ-site tumors or its microenvironments is not fully established. To understand the role of each galectin in lung, colon, pancreas and urinary bladder tumors and their relevance as markers of tumor progression; chemoprevention intervention trials was evaluated. Lung adenoma and adenocarcinomas were induced by tobacco specific carcinogen, NNK and colon adenomas and adenocarcinomas by azoxymethane (AOM). Whereas, pancreatic ductal tumors were induced by KrasG12D activation in p48Cre.KrasG12D mice and bladder tumors were induced by SV40 activation in UPII-SV40T mice. Expression profiling of galectins was obtained by whole genome-transcriptome analysis with SOLiD methodology from RNAs of tumors and normally appearing tissues from each organ-site. Further profiling and characterization of each galectin (Gal) was carried by RT-PCR, western blotting, and immunohistochemcial analysis. Data from transcriptome suggest that Gal-1, Gal-3, Gal-4, and Gal-12 are significantly associated with tumor progression. Particularly, Gal-1, Gal-3, and Gal-4 expressions were positively correlated with tumor progression in all the above cancers compared to their respective normal tissues and early lesions. Gal-12 was significantly increased in pancreatic and bladder tumor tissues but not in lung and colonic tumors. To understand prognostic value of galectins for chemoprevention interventions, we tested well-established and highly efficacious agents, difluoromethyl ornithine (DFMO), an inhibitor of ODC), and Licofelone, a dual COX-LOX inhibitor in above organ site cancers. DFMO (up to 2,000 ppm) and Licofelone (up to 500 ppm) was administered in the diet to mice after initiation of preneoplastic lesions or adenomas and continued until malignant tumor formations. As anticipated, both agents significantly inhibited malignant tumor formation. Importantly, intervention of tumor growth with mice fed with chemopreventive agents (DFMO and licofelone) showed a significant decrease in expression of Gal-3 and Gal-4 in tumor tissues and correlated with progression of tumor growth inhibition. Overall, these data provide impetus for further studies to delineate the role of Gal-3 and Gal-4 in various cancers and their usefulness as prognostic markers of chemoprevention interventions. (Supported by Kerley-Cade Chair Endowment and NCI-N01-CN-53300) Citation Format: Gaurav Kumar, Venkateshwar Madka, Altaf Mohammed, Jagan M. r. Patolla, Naveena B. Janakiram, Qian Li, Yuting Zhang, Laura Biddick, Allison Gillaspy, Stanley Lightfoot, Chinthalapally V. Rao. Galectin-3 and -4 as signature markers of lung, colon, pancreatic and bladder tumor progression and chemopreventive interventions. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1905. doi:10.1158/1538-7445.AM2015-1905

Introduction: Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death worldwide. Chronic infections with hepatitis B or C viruses are the leading cause of HCC. The cancer stem cell (CSC) marker, doublecortin-like kinase (DCLK1), is believed to be a key factor for the development of multiple cancer types including HCC. However, its impact on signaling pathways that promote hepatocarcinogenesis is largely unknown. We have shown DCLK1's enhanced expression in HCC and its stimulatory role in hepatitis C virus (HCV) replication. Our published reports further suggest that DCLK1 positively affects tumor-related miRNAs and transcription factors that promote epithelial-mesenchymal transition (EMT). These observations prompted us to investigate DCLK1 signaling module in virus-induced liver pathogenesis and HCC. Methods: Genome-wide transcriptome analysis was carried out in total RNAs isolated from DCLK1-overexpressing and control hepatoma cells. One hundred five clinical cases representing various stages of liver diseases in patients with chronic hepatitis B or C were analyzed for an array of markers including DCLK1 by immunohistochemical staining and Western blot. Huh7 hepatoma cells were transplanted into the flanks of athymic nude mice to generate HCC-like tumor xenografts. The tumors were analyzed for proteins, mRNAs and miRNAs or treated with siRNA against DCLK1 and scrambled siRNA to monitor tumor growth arrest. Results: We found that the expression of 19 genes (14 upregulated, 5 downregulated) was specifically affected by DCLK1 overexpression in hepatoma cell lines. Among these, the level of kinase-suppressor of Ras 1 (KSR1) scaffold protein of Ras-MAPK pathway was increased significantly when recombinant DCLK1 was co-expressed with HCV replicon. Examination of liver tissues derived from patients with chronic hepatitis B/C and HCC suggests that a pro-inflammatory S100A9 protein tends to correlate with DCLK1 overexpression in cirrhosis with or without HCC. Both DCLK1 and S100A9 proteins were mainly localized in the regenerative nodules, fibrotic septa, mesenchymal cells, endothelium and areas with lymphocytes aggregates. Analysis of tumor xenografts developed by hepatoma cells suggest that overexpression of DCLK1 is accompanied by high-level expression of S100A9 and c-Myc as well as activation of NFκB. Conversely, siRNA-led inhibition of DCLK1 causes decrease in tumor volume considerably in a xenograft model. Conclusions: DCLK1 overexpression appears to be intimately related to the activation of pro-inflammatory and MAPK signaling pathways during the development of virus-induced pre-neoplastic conditions and initiation of tumors in liver. Thus, targeting DCLK1 at early stage of liver diseases may prevent virus-induced cirrhosis and HCC. Citation Format: Naushad Ali, Parthasarathy Chandrakesan, Mark Huycke, Sanam Husain, Allison F. Gillaspy, Randal May, William L. Berry, Sripathi Sureban, Dongfeng Qu, Nathaniel Weygant, Michael S. Bronze, Danny N. Dhanasekaran, Courtney W. Houchen. Overexpression of a cancer stem cell marker doublecortin-like kinase (DCLK1) leads to activation of inflammatory cascade during development of virus-induced hepatocellular carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3171. doi:10.1158/1538-7445.AM2014-3171

Introduction: Epithelial ovarian cancer is heterogeneous, with subgroups defined by cell of origin (ovary vs. fallopian tube), histology, and carcinogenic pathway (the etiologic pathway through which tumors arise: type I tumors develop on the ovarian surface and are low grade serous or mucinous histology; type II tumors develop through endometriotic implantation and are clear cell or endometrioid histology; type III tumors originate in the fallopian tube and are high grade serous histology). Although differences in associations have been observed with risk of incident ovarian cancer, few studies have examined differences in survival by subtype. In the New England Case-Control Study of ovarian cancer (NECC), we examined differences in survival by tumor dominance (a surrogate for cell of origin), histology, and carcinogenic pathway. Methods: Among 2076 women with epithelial ovarian cancer (1991-2008), 892 deaths were observed. Cox proportional hazards regression was used to calculate hazards ratios (HRs) and 95% confidence intervals (95% CI) for the association of ovarian cancer subtype with overall survival, adjusting for age at diagnosis, study phase, year of diagnosis (as a proxy for treatment), BMI, and smoking status. Results: Serous invasive tumors were more likely to be non-dominant (likely fallopian origin) and type III. Compared to serous invasive tumors, all other tumor histologies had statistically significantly improved survival. Similarly, dominant tumors (i.e., likely ovarian origin) had greater survival than non-dominant tumors (HR: 0.38; 95% CI: 0.31-0.47). Type I (mucinous and low grade serous) and type II (endometrioid and clear cell) tumors had better survival than type III (high grade serous) tumors (HR: 0.21; 95%CI: 0.16-0.28 and HR: 0.23; 95% CI: 0.18-0.29, respectively). Conclusion: Regardless of how subtype was defined, high grade, invasive serous tumors had worse survival compared to other tumor subtypes. This underscores the need for prevention and treatment targeted at these aggressive tumors. Table.Associations between tumor subtype and overall survivalSubtypeDeaths/CasesMedian Survival (years)HR (95% CI)HistologySerous invasive654/9683.21.00 (ref.)Serous borderline25/25010.10.35 (0.18-0.67)Mucinous36/2427.10.38 (0.25-0.58)Endometrioid68/3314.70.28 (0.21-0.37)Clear cell29/1163.40.30 (0.21-0.44)DominanceNon-dominant268/3853.31.00 (ref.)Dominant162/6034.00.38 (0.31-0.47)PathwayType III596/8563.21.00 (ref.)Type II97/4474.00.23 (0.18-0.29)Type I60/2915.70.21 (0.16-0.28) Citation Format: Elizabeth M. Poole, Daniel W. Cramer, Allison F. Vitonis, Kathryn L. Terry. Ovarian cancer survival by tumor subtype. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4124. doi:10.1158/1538-7445.AM2014-4124

Differences in ovarian cancer incidence rates worldwide suggest an important role for lifestyle factors, including diet, that may influence disease risk. In the WHI dietary modification RCT, a low-fat diet reduced ovarian cancer risk. However, a pooled analysis of 12 cohort studies observed no association between total fat intake and ovarian cancer risk. We hypothesized that the association between dietary fat intake and ovarian cancer risk may vary between the histological subtypes, or that associations may differ depending on the type of fat consumed, such as saturated fat, which has deleterious health effects, and long-chain omega-3 fatty acids, which have anti-inflammatory properties. The study objective was to evaluate fat intake in a New England case-control study that included 1872 cases and 1978 population-based controls enrolled between 1992-2008. At the time of enrolment, participants were interviewed in-person about known and suspected ovarian cancer risk factors and diet was assessed using a validated self-administered, semi-quantitative FFQ. Unconditional logistic regression was used to estimate the association between fat intake and ovarian cancer risk overall and polytomous logistic regression was used to test whether risk associations varied across the histological subtypes of invasive ovarian cancer. Multivariate models were adjusted for study center and phase, age, number of pregnancies, oral contraceptive use, history of tubal ligation and family history of ovarian cancer. We observed a significantly decreased risk of ovarian cancer overall with higher intakes of omega-3 and omega-6 (long chain n-3, Q4 vs. Q1, OR = 0.79, 95% CI = 0.66 - 0.96; total n-6, Q4 vs. Q1, OR = 0.77, 95% CI = 0.64 - 0.94), and an increased risk with increased consumption of total trans fats (Q4 vs. Q1, OR = 1.30, 95% CI = 1.08 - 1.57). The protective effects for high intake of omega-3 were strongest for endometrioid invasive tumors (Q4 vs. Q1, OR = 0.58, 95% CI = 0.41 - 0.82, Ptrend = 0.003, Phet (differences in associations between all invasive histological subtypes) = 0.20). There was a suggestive increased risk for serous, endometrioid, and mucinous invasive tumors with high intake of trans fats although this association was significant only for serous tumors (Q4 vs. Q1, OR = 1.28, 95% CI = 1.02 - 1.62, Ptrend = 0.02, Phet = 0.83). The protective effects of omega-6 were no longer apparent in analyses of different histological subtypes of invasive ovarian cancer although we observed an inverse association with risk of serous borderline tumors (Q4 vs. Q1, OR = 0.56, 95% CI = 0.36 - 0.90, Ptrend = 0.05). These findings suggest that higher intakes of omega-3 may be protective for ovarian cancer, while high consumption of trans fats appeared to increase risk. To further evaluate the possible role for omega-3 in the prevention of ovarian cancer, additional studies are needed to confirm these findings and to investigate the mechanistic basis for these associations. Citation Format: Melissa A. Merritt, Daniel W. Cramer, Allison F. Vitonis, Stacey A. Missmer, Linda J. Titus, Kathryn L. Terry. Dietary fat intake and risk of epithelial ovarian cancer by tumor histology. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 148. doi:10.1158/1538-7445.AM2013-148

Glioblastoma multiforme (GBM) is a lethal brain cancer with a life expectancy of only 12-15 months. Current standard treatment for GBM is surgery and chemoradiation. However, there are many difficulties when it comes to treating this aggressive brain cancer due to the inherent radio- and chemo-resistance. Consequently, there is a critical need for new therapeutic approaches to make radiation/chemotherapy more effective. Ataxia telangiectasia (A-T) patients are extremely sensitive to ionizing radiation. The protein mutated in A-T, ATM (A-T mutated), controls the cells’ response to radiation, referred to as the DNA damage response (DDR). ATM is a master protein kinase that targets many proteins during the DDR including regulators of cell cycle checkpoints, DNA repair, and apoptosis. In addition, without any radiation, ATM might regulate glioma dispersal. Using a highly specific inhibitor of the ATM kinase (ATMi), we recently showed that ATM regulates both the ERK and AKT signaling pathways and controls glioma cell migration and invasion in vitro. To take these studies further we have now used a genetic approach and knocked down ATM in human glioma cells. We have recapitulated our previous finding with an ATMi and shown that ATM knockdown glioma cells have reduced ability to migrate in vitro. In order to determine whether MEK/ERK and/or AKT regulate migration, human glioma cells were exposed to a MEK (PD0325901) or an AKT (MK-2266) inhibitor in a ‘scratch-assay’. We found that only the former compound affected migration in vitro. Hence, we have shown that ATM regulates glioma migration in vitro, perhaps via MEK/ERK. On the other hand, ATM might regulate invasion via AKT. The signaling relationship in vitro between ATM, ERK, and AKT is currently being investigated. Furthermore, ongoing studies will establish whether ERK and AKT signaling affect migration and invasion in vivo. Citation Format: Jasmine L. Allen, Allison F. Wagner, Jason M. Beckta, James Watson, Sarah E. Golding, Kristoffer C. Valerie. ATM regulates glioma migration via MEK-ERK not AKT. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 437. doi:10.1158/1538-7445.AM2013-437 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.

Purpose: MUC16 is a cell surface mucin that is expressed at high levels by epithelial ovarian tumors, and is detected in serum as the CA125 antigen. MUC16 is clinically used as a tumor marker in the management of ovarian cancer and has been associated with prognosis. MUC16 is also thought to play an important role in ovarian tumor cell survival and metastasis. We studied the association of four tagging SNPs of the MUC16 gene (rs2547065 (C/G), rs1559168 (A/T), rs2121133 (A/G), rs2121133 (A/G)) and risk of ovarian cancer as well as the correlation of these SNPs with CA125 levels. Methods: MUC16 polymorphisms were genotyped using blood samples collected from 760 women diagnosed with ovarian cancer and 788 healthy controls enrolled in the New England Case-Control Study between 2003 and 2008. 388 cases had preoperative CA125 levels abstracted from medical records. Odds ratios and 95%CIs were calculated using logistic regression; polytomous (multinomial) logistic regression was used to estimate multivariate odds ratios by ovarian cancer histological subtype. The association between log normalized pre-operative CA125 levels and MUC 16 SNPs was evaluated using generalized linear models. Results: A significant association was observed between the rs2547065 polymorphism and ovarian cancer risk (per allele: OR=1.30, 95% CI: 1.11-1.52). The risk was greatest for women carrying two copies of the variant allele (OR=1.78, 95% CI: 1.29-2.45). When stratified by histological subtype, these associations were most apparent in the recessive model for women with serous invasive (OR = 1.69; 95%CI: 1.15-2.48) and clear cell (2.49 95% CI: 1.13-5.52) tumors. There were no significant associations between the other three MUC16 SNPs (rs1559168, rs2121133, rs12984471) and ovarian cancer risk. The rs2547065 polymorphism was not found to be associated with pre-operative CA125 levels in cases overall or in the subset of women with serous and clear cell cancers. Conclusions: These results suggest that women who carry one or more variant alleles of MUC16 SNP rs2547065 have an increased risk of ovarian cancer of the serous invasive and clear cell histological subtype. Further study of MUC 16 SNPs in relation to risk of ovarian cancer and their effect on CA125 levels is warranted. Citation Format: Kristina Williams, Kathryn Terry, Allison Vitonis, Daniel Cramer. Genetic variations in the MUC16 gene encoding tumor marker CA125 and their association with the risk of epithelial ovarian cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1342. doi:10.1158/1538-7445.AM2013-1342

The identification of modifiable risk factors for ovarian cancer is important to reduce incidence and mortality. Previous studies have suggested that the lactose component of dairy foods may promote ovarian carcinogenesis via the accumulation of galactose (lactose metabolite) with potentially toxic effects on oocytes and disruption of ovarian/ pituitary feedback. Alternatively, high calcium levels in dairy products might decrease ovarian cancer risk by decreasing cell proliferation and increasing apoptosis by down-regulation of parathyroid hormone which has opposing effects. Our objective was to evaluate whether dairy foods and nutrients were associated with ovarian cancer risk in 1909 epithelial ovarian cancers and 1989 population based controls identified between 1992-2008 in the New England based case-control (NECC) study. At the time of enrollment, participants were interviewed in-person about known and suspected ovarian cancer risk factors and diet was assessed using a validated self-administered, semi-quantitative food frequency questionnaire. We used unconditional logistic regression to estimate associations between dairy exposures and ovarian cancer risk and polytomous logistic regression to test whether associations varied across histological subtypes of ovarian cancer or in cases that were classified as rapidly fatal vs. less aggressive cases. Multivariate models were adjusted for study center/phase, age, number of pregnancies, oral contraceptive use, tubal ligation, family history of ovarian cancer and total calories. We observed a significantly decreased risk of ovarian cancer with higher intakes of dietary and total (diet + supplements) calcium (dietary calcium: Quartile 4 (Q4) vs. Q1 OR= 0.74 (95% confidence interval (CI) = 0.62 - 0.89); total calcium: Q4 vs. Q1 OR = 0.61 (95% CI = 0.50 - 0.74)), Ptrend < 0.001 in both comparisons. Higher intakes of dietary and total vitamin D also were associated with a modest but statistically significant decreased risk of ovarian cancer (dietary vit D: Q4 vs. Q1 OR=0.82 (95% CI = 0.68 - 0.99); total vit D: Q4 vs. Q1 OR = 0.76 (95% CI = 0.63 - 0.92), Ptrend= 0.03 and 0.01 for dietary and total vitamin D, respectively. In models that were mutually adjusted for total calcium, total vitamin D and lactose, the association with calcium retained significance while the association with vitamin D was no longer significant. We did not observe an association between lactose and ovarian cancer risk and we observed similar associations for calcium, vitamin D and lactose among case groups defined as rapidly fatal or less aggressive. Together these results confirm previous reports that calcium appears to be protective for ovarian cancer. Prior studies of vitamin D and ovarian cancer risk have been inconsistent, however we observed a modest protective association that warrants further consideration. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 660. doi:1538-7445.AM2012-660

Introduction: An association between talc powder use in the genital area and ovarian cancer has been repeatedly observed but repeatedly challenged because of a “weak” overall association and apparent lack of dose-response. To determine whether these aspects of the association have been affected by the failure to consider, in a uniform fashion, histologic type of ovarian cancer, menopausal status, or family history, we examined data from our own case-control studies including a new series of 845 cases and 857 controls. Methods: We combined data from 3 phases of our case-control study of ovarian cancer that includes data on 2074 ovarian cancer cases and 2101 controls from eastern Massachusetts and New Hampshire recruited between 1992 and 2008. We used logistic regression to study the association between ovarian cancer and regular use of genital talc as well as total applications (estimated from frequency and duration of use), adjusted for study phase and center, age, parity, oral contraceptive use, tubal ligation, BMI, Jewish ethnicity, and family history of breast or ovarian cancer. Separate analyses were done for all ovarian cancer cases, non-mucinous invasive cases, and serous invasive cases. Results: The association of ovarian cancer with genital talc use [OR (and 95% CL)] was 1.30 (1.14, 1.50) for all cases, 1.37 (1.18, 1.59) for non-mucinous invasive cases, and 1.42 (1.17, 1.73) for invasive serous cases. A dose-response based on control quartiles for total applications was also present, p trend = 0.001, 0.0004, 0.001 for all, non-mucinous invasive, and invasive serous cases, respectively. However, the dose-response differed strikingly for pre- and postmenopausal women, p-heterogeneity = 0.07, 0.009, 0.002 for all, non-mucinous invasive, and invasive serous cases, respectively. The dose-response was more apparent for premenopausal women, and relatively flat for postmenopausal women. Further analyses showed that exclusion of cases with a possible familial disease further improved the dose-response, especially in premenopausal women with invasive serous cancer in whom the odds ratios (and 95% limits) were 2.22 (1.23, 4.02) for about 2000 to 8400 applications and 3.23 (1.52, 6.89) for women with greater than 8400 applications, compared to women with no use. Conclusion: The failure to take into consideration histologic type of ovarian cancer in a systematic fashion has led to both an under estimation of the overall effect in all women and the dose-response in premenopausal women, especially those without a family history. Repeating analyses in existing data sets may help clarify the still-debated association between talc and ovarian cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-446. doi:10.1158/1538-7445.AM2011-LB-446

The loss of BRCA1 function may induce profound transcriptional changes, phenotypic reprogramming and ultimately, generate genetically unstable tumor-initiating cells, which significantly increase the risk of breast and ovarian cancer. The molecular targets and pathways involved in early events of malignant transformation of at-risk epithelium has not been well investigated, particularly the effects of chronic inflammation. In an earlier study, we demonstrated that platelet activating factor (PAF), a potent pro-inflammatory mediator, plays a significant role in ovarian cancer progression and invasion (Cancer Research, 68:5839, 2008). Here, we extend our finding to show that PAF receptor is over expressed in BRCA1-mutated (BRCA1+) human ovarian surface epithelial cells (HOSE) by western blot and in distal fallopian tube (fimbria) epithelial cells by immunohistochemistry. In addition, PAF induced cell apoptosis only in wild type HOSE cells, and anti-apoptosis in BRCA1+ ovarian surface epithelial cells. A kinase microarray revealed that phosphor-STAT1/3/4/6 was simultaneously activated by 100 nM PAF treatment in BRCA1+ ovarian cancer cells. Induction of phosphor-STAT1 associated with PAFR and BRCA1-mutation was further confirmed in three BRCA1+ HOSE cell lines, but not in normal (HOSEE6E7) or malignant (OVCA429) ovarian epithelial cells. Co-immune precipitation revealed that PAF/PAFR coordinately activates FAK through dephosphorylation and STAT1 through phosphorylation only in BRCA1+ ovarian epithelial cells. These findings strongly suggest that potent inflammatory mediators (i.e. PAF) may play a significant role to induce malignant transformation in BRCA1-mutant ovarian epithelial cells through the FAK-STAT pathway. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4668.