Publications by authors named "Shannon Maclaughlan"

9 Publications

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Expression profiling of primary and metastatic ovarian tumors reveals differences indicative of aggressive disease.

PLoS One 2014 14;9(4):e94476. Epub 2014 Apr 14.

Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Southern Illinois University School of Medicine, Springfield, Illinois, United States of America.

The behavior and genetics of serous epithelial ovarian cancer (EOC) metastasis, the form of the disease lethal to patients, is poorly understood. The unique properties of metastases are critical to understand to improve treatments of the disease that remains in patients after debulking surgery. We sought to identify the genetic and phenotypic landscape of metastatic progression of EOC to understand how metastases compare to primary tumors. DNA copy number and mRNA expression differences between matched primary human tumors and omental metastases, collected at the same time during debulking surgery before chemotherapy, were measured using microarrays. qPCR and immunohistochemistry validated findings. Pathway analysis of mRNA expression revealed metastatic cancer cells are more proliferative and less apoptotic than primary tumors, perhaps explaining the aggressive nature of these lesions. Most cases had copy number aberrations (CNAs) that differed between primary and metastatic tumors, but we did not detect CNAs that are recurrent across cases. A six gene expression signature distinguishes primary from metastatic tumors and predicts overall survival in independent datasets. The genetic differences between primary and metastatic tumors, yet common expression changes, suggest that the major clone in metastases is not the same as in primary tumors, but the cancer cells adapt to the omentum similarly. Together, these data highlight how ovarian tumors develop into a distinct, more aggressive metastatic state that should be considered for therapy development.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0094476PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3986100PMC
January 2015

HE4 (WFDC2) gene overexpression promotes ovarian tumor growth.

Sci Rep 2014 Jan 6;4:3574. Epub 2014 Jan 6.

Molecular Therapeutics Laboratory, Program in Women's Oncology, Women and Infants' Hospital of Rhode Island, Alpert Medical School, Brown University, Providence, RI 02903, USA.

Selective overexpression of Human epididymal secretory protein E4 (HE4) points to a role in ovarian cancer tumorigenesis but little is known about the role the HE4 gene or the gene product plays. Here we show that elevated HE4 serum levels correlate with chemoresistance and decreased survival rates in EOC patients. HE4 overexpression promoted xenograft tumor growth and chemoresistance against cisplatin in an animal model resulting in reduced survival rates. HE4 displayed responses to tumor microenvironment constituents and presented increased expression as well as nuclear translocation upon EGF, VEGF and Insulin treatment and nucleolar localization with Insulin treatment. HE4 interacts with EGFR, IGF1R, and transcription factor HIF1α. Constructs of antisense phosphorothio-oligonucleotides targeting HE4 arrested tumor growth in nude mice. Collectively these findings implicate increased HE4 expression as a molecular factor in ovarian cancer tumorigenesis. Selective targeting directed towards the HE4 protein demonstrates therapeutic benefits for the treatment of ovarian cancer.
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http://dx.doi.org/10.1038/srep03574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3880958PMC
January 2014

PT19c, Another Nonhypercalcemic Vitamin D2 Derivative, Demonstrates Antitumor Efficacy in Epithelial Ovarian and Endometrial Cancer Models.

Genes Cancer 2013 Nov;4(11-12):524-34

Molecular Therapeutics Laboratory, Program in Women's Oncology, Department of Obstetrics and Gynecology, Women and Infants' Hospital, Brown University, Providence, RI, USA.

Hypercalcemia remains a major impediment to the clinical use of vitamin D in cancer treatment. Approaches to remove hypercalcemia and development of nonhypercalcemic agents can lead to the development of vitamin D-based therapies for treatment of various cancers. In this report, in vitro and in vivo anticancer efficacy, safety, and details of vitamin D receptor (VDR) interactions of PT19c, a novel nonhypercalcemic vitamin D derived anticancer agent, are described. PT19c was synthesized by bromoacetylation of PTAD-ergocalciferol adduct. Broader growth inhibitory potential of PT19c was evaluated in a panel of chemoresistant breast, renal, ovarian, lung, colon, leukemia, prostate, melanoma, and central nervous system cancers cell line types of NCI60 cell line panel. Interactions of PT19c with VDR were determined by a VDR transactivation assay in a VDR overexpressing VDR-UAS-bla-HEK293 cells, in vitro VDR-coregulator binding, and molecular docking with VDR-ligand binding domain (VDR-LBD) in comparison with calcitriol. Acute toxicity of PT19c was determined in nontumored mice. In vivo antitumor efficacy of PT19c was determined via ovarian and endometrial cancer xenograft experiments. Effect of PT19c on actin filament organization and focal adhesion formation was examined by microscopy. PT19c treatment inhibited growth of chemoresistant NCI60 cell lines (log10GI50 ~ -4.05 to -6.73). PT19c (10 mg/kg, 35 days) reduced growth of ovarian and endometrial xenograft tumor without hypercalcemia. PT19c exerted no acute toxicity up to 400 mg/kg (QDx1) in animals. PT19c showed weak VDR antagonism, lack of VDR binding, and inverted spatial accommodation in VDR-LBD. PT19c caused actin filament dysfunction and inhibited focal adhesion in SKOV-3 cells. PT19c is a VDR independent nonhypercalcemic vitamin D-derived agent that showed noteworthy safety and efficacy in ovarian and endometrial cancer animal models and inhibited actin organization and focal adhesion in ovarian cancer cells.
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http://dx.doi.org/10.1177/1947601913507575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3877664PMC
November 2013

Identification of ovarian cancer metastatic miRNAs.

PLoS One 2013 12;8(3):e58226. Epub 2013 Mar 12.

Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island, USA.

Serous epithelial ovarian cancer (EOC) patients often succumb to aggressive metastatic disease, yet little is known about the behavior and genetics of ovarian cancer metastasis. Here, we aim to understand how omental metastases differ from primary tumors and how these differences may influence chemotherapy. We analyzed the miRNA expression profiles of primary EOC tumors and their respective omental metastases from 9 patients using miRNA Taqman qPCR arrays. We find 17 miRNAs with differential expression in omental lesions compared to primary tumors. miR-21, miR-150, and miR-146a have low expression in most primary tumors with significantly increased expression in omental lesions, with concomitant decreased expression of predicted mRNA targets based on mRNA expression. We find that miR-150 and miR-146a mediate spheroid size. Both miR-146a and miR-150 increase the number of residual surviving cells by 2-4 fold when challenged with lethal cisplatin concentrations. These observations suggest that at least two of the miRNAs, miR-146a and miR-150, up-regulated in omental lesions, stimulate survival and increase drug tolerance. Our observations suggest that cancer cells in omental tumors express key miRNAs differently than primary tumors, and that at least some of these microRNAs may be critical regulators of the emergence of drug resistant disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0058226PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3595263PMC
September 2013

Necrotizing infection of the breast after core needle biopsy.

Breast J 2013 Mar-Apr;19(2):201-2. Epub 2013 Jan 7.

Department of Obstetrics & Gynecology, Women and Infants' Hospital, The Warren Alpert Medical School of Brown University, Providence, Rhode Island 02905, USA.

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http://dx.doi.org/10.1111/tbj.12088DOI Listing
September 2013

Correlation between smoking status and cervical cancer screening: a cross-sectional study.

J Low Genit Tract Dis 2011 Apr;15(2):114-9

Warren Alpert Medical School, Brown University, Providence, RI, USA.

Objectives: Tobacco use is a risk factor for the development and progression of cervical cancer. The purpose of this study was to determine the correlation between smoking status among women and their compliance with cervical cancer screening guidelines.

Materials And Methods: A cross-sectional analysis of the Behavioral Risk Factor Surveillance System was performed using the 2006 survey data. Women with no history of hysterectomy who answered the questions regarding smoking status, age, and last Pap smear were included (n = 150,786). Data were weighted for survey design.

Results: The overall prevalence of compliance with cervical cancer screening guidelines was 83.9%. The rate of compliance was highest among former smokers (86.7%) compared with never smokers (83.7%) and current smokers (81.7%; p < .001). Among women aged 21 to 65 years, the odds of current smokers having had a Pap test in the past 3 years was 0.70 compared with women who never smoked (95% confidence interval = 0.63-0.77), when controlled for marital status, income, and access to health care. The odds of former smokers complying with screening guidelines were similar to women who never smoked.

Conclusions: Women who smoke are at higher risk for developing cervical cancer but have a lower rate of screening for the disease. Efforts to increase prevalence of Pap test compliance should target current smokers.
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http://dx.doi.org/10.1097/LGT.0b013e3181f58d0dDOI Listing
April 2011

Current clinical use of biomarkers for epithelial ovarian cancer.

Curr Opin Oncol 2010 Sep;22(5):492-7

Department of Obstetrics and Gynecology, Women and Infants' Hospital, Brown University, Providence, RI 02905, USA.

Purpose Of Review: The majority of women diagnosed with epithelial ovarian cancer (EOC) will be diagnosed with advanced stage disease, a stage that is fundamentally incurable. Survival rates for this deadly disease have improved over the last 25 years secondarily to the advances in surgery and chemotherapeutics. Effective screening protocols are not currently available, and risk assessment protocols for the presence of EOC in women with an ovarian cyst need improvement. Earlier diagnosis may result in stage migration and decreased morbidity for women diagnosed with EOC. Better risk assessment will allow the triage of women to centers of excellence in the treatment and management of ovarian cancer with improved outcomes and survival rates. This review will focus on new biomarkers and algorithms for screening and risk assessment for ovarian cancer.

Recent Findings: The use of multiple biomarkers and statistical algorithms has been shown to be an accurate method for assessing the risk of ovarian cancer in women with ovarian cysts/masses preoperatively. Newer algorithms employing biomarkers to trigger ultrasound imaging for screening also show promise. The addition of novel biomarkers such as human epididymis protein 4 to the use of CA125 improves the sensitivity and specificity over that of either biomarker alone for the management of EOC.

Summary: For more than 25 years CA125 has been the main biomarker for the management of women with EOC. Recently, novel biomarkers have become available clinically that improve upon the use of CA125 for the risk assessment and management of women with ovarian cancer.
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http://dx.doi.org/10.1097/CCO.0b013e32833c3351DOI Listing
September 2010

Current state of biomarker development for clinical application in epithelial ovarian cancer.

Gynecol Oncol 2010 Feb 31;116(2):240-5. Epub 2009 Oct 31.

Program in Women's Oncology, Department of Obstetrics and Gynecology, Women and Infants' Hospital, Alpert Medical School, Brown University, Providence, RI, USA.

Each year in the United States over 15,000 women die of epithelial ovarian cancer (EOC) and 22,000 are diagnosed with the disease. The incidence of ovarian cancer has remained stable over the past decade however, survival rates have improved steadily. Increases in survival rates can be attributed to the advances in surgical management, development of effective cytotoxic drugs and the route of administration of chemotherapy. Ovarian cancer survival rates could also be improved through screening and early detection. Disappointingly, effective screening methods have not been established and continue to be elusive. Historically the goal of a screening test was to achieve a positive predictive value (PPV) greater than 10% in order be considered cost effective and have an acceptable risk for the population being screened. Despite the inability of currently available screening algorithms to achieve the desired PPV there may be an advantage in producing a stage migration to lower stages at the time of diagnoses, thereby resulting in improved survival. Equally important recent studies have demonstrated that women who have their initial surgery performed by gynecologic oncologists, and women who have their surgeries at centers experienced in the treatment of ovarian cancer have higher survival rates. For these reasons it is essential that all women at high risk for ovarian cancer receive their initial care by gynecologic oncologists and at centers with multidisciplinary teams experienced in the optimal care of ovarian cancer patients. With this in mind, methods that facilitate the accurate triage of women who will ultimately be diagnosed with ovarian cancer could play a significant role in improving survival rates for these patients. This review article will examine the current state of biomarker use in ovarian cancer screening, risk assessment and for monitoring ovarian cancer patients.
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http://dx.doi.org/10.1016/j.ygyno.2009.09.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3134885PMC
February 2010

Endometrial expression of Cyr61: a marker of estrogenic activity in normal and abnormal endometrium.

Obstet Gynecol 2007 Jul;110(1):146-54

Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA.

Objective: To compare the expression of Cyr61 in normal cycling endometrium with endometrium from women with polycystic ovarian syndrome (PCOS) and endometrial hyperplasia and adenocarcinoma.

Methods: This is a retrospective study of 59 samples of normal and abnormal endometrium. Endometrial biopsies were obtained from normal fertile controls throughout the menstrual cycle and compared with endometrium from ovulatory and anovulatory women with PCOS and complex endometrial hyperplasia and endometrioid adenocarcinoma. Cyr61 expression was evaluated by using immunohistochemistry and reverse transcription PCR for Cyr61, estrogen receptor (ER)-alpha, a marker of cell proliferation (Ki67), and another marker of early estrogen action, cFos. Regulation of Cyr61 protein was studied in a steroid-responsive endometrial carcinoma cell line, ECC1.

Results: Cyr61 protein was regulated by estrogen. In normal endometrium, Cyr61 was highest in the proliferative phase and lowest in the normal midsecretory phase. In contrast, elevated levels of Cyr61, ER-alpha, Ki67, and cFos were all found in the midsecretory endometrium of ovulatory PCOS patients, endometrial cancer patients, and hyperplasia patients.

Conclusion: Cyr61 is overexpressed in PCOS endometrium, reflecting a heightened responsiveness to estrogen. As a unique marker of estrogen action, Cyr61 may be an early biomarker for the development of hyperplasia or adenocarcinoma in this group of women.
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http://dx.doi.org/10.1097/01.AOG.0000269047.46078.28DOI Listing
July 2007