Browsing by Subject "cancers"

Now showing 1 - 4 of 4
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    The emerging role of zinc transporters in cellular homeostasis and cancer
    (Nature Publishing group, 2017-07-28) Bafaro, Elizabeth; Liu, Yuting; Xu, Yan; Dempski, Robert E; Obstetrics and Gynecology, School of Medicine
    Zinc is an essential micronutrient that plays a role in the structural or enzymatic functions of many cellular proteins. Cellular zinc homeostasis involves the opposing action of two families of metal transporters: the ZnT (SLC30) family that functions to reduce cytoplasmic zinc concentrations and the ZIP (SLC39) family that functions to increase cytoplasmic zinc concentrations. Fluctuations in intracellular zinc levels mediated by these transporter families affect signaling pathways involved in normal cell development, growth, differentiation and death. Consequently, changes in zinc transporter localization and function resulting in zinc dyshomeostasis have pathophysiological effects. Zinc dyshomeostasis has been implicated in the progression of cancer. Here we review recent progress toward understanding the structural basis for zinc transport by ZnT and ZIP family proteins, as well as highlight the roles of zinc as a signaling molecule in physiological conditions and in various cancers. As zinc is emerging as an important signaling molecule in the development and progression of cancer, the ZnT and ZIP transporters that regulate cellular zinc homeostasis are promising candidates for targeted cancer therapy.
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    HOXB13 Mediates Tamoxifen Resistance and Invasiveness in Human Breast Cancer by Suppressing ERα and Inducing IL-6 Expression
    (American Association for Cancer Research, 2013-09-01) Shah, Nilay; Jin, Kideok; Cruz, Leigh-Ann; Park, Sunju; Sadik, Helen; Cho, Soonweng; Goswami, Chirayu Pankaj; Nakshatri, Harikrishna; Gupta, Rajnish; Chang, Howard Y.; Zhang, Zhe; Cimino-Mathews, Ashley; Cope, Leslie; Umbricht, Christopher; Sukumar, Saraswati
    Most breast cancers expressing the estrogen receptor α (ERα) are treated successfully with the receptor antagonist tamoxifen (TAM), but many of these tumors recur. Elevated expression of the homeodomain transcription factor HOXB13 correlates with TAM-resistance in ERα-positive (ER+) breast cancer, but little is known regarding the underlying mechanism. Our comprehensive evaluation of HOX gene expression using tiling microarrays, with validation, showed that distant metastases from TAM-resistant patients also displayed high HOXB13 expression, suggesting a role for HOXB13 in tumor dissemination and survival. Here we show that HOXB13 confers TAM resistance by directly downregulating ERα transcription and protein expression. HOXB13 elevation promoted cell proliferation in vitro and growth of tumor xenografts in vivo. Mechanistic investigations showed that HOXB13 transcriptionally upregulated interleukin (IL)-6, activating the mTOR pathway via STAT3 phosphorylation to promote cell proliferation and fibroblast recruitment. Accordingly, mTOR inhibition suppressed fibroblast recruitment and proliferation of HOXB13-expressing ER+ breast cancer cells and tumor xenografts, alone or in combination with TAM. Taken together, our results establish a function for HOXB13 in TAM resistance through direct suppression of ERα and they identify the IL-6 pathways as mediator of disease progression and recurrence.
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    The IUPUI Center for HPV Research: Updates 2014-2015
    (Office of the Vice Chancellor for Research, 2015-04-17) Zimet, Gregory D.; Fortenberry, J. Dennis
    Background: Human papillomavirus (HPV) is a very common infection. High risk (HR) HPV types (particularly types 16 & 18) are causally implicated in many cancers, including cervical, anal, vaginal, vulvar, penile, and head and neck cancers. In an effort to address the problems associated with HPV infection and prevention, the Center for HPV Research at IUPUI (Zimet & Fortenberry, Co-Directors) fosters collaboration among investigators from multiple disciplines and departments at IUPUI, IU Bloomington, Purdue University, and University of Notre Dame. There currently are 32 faculty and 8 pre- and post-doctoral fellows who are members of the Center. The Center for HPV Research was established in July, 2012 with funds from the IUPUI Signature Center Initiative, the Department of Pediatrics, and the IU Simon Cancer Center. Over the past year, Center members had 6 external & internal grants funded, 5 additional grants submitted, 8 peer-reviewed articles published, and gave over 20 scientific conference and invited presentations. In this abstract we highlight a study representing a collaboration among 5 center members, with Dr. Marcia Shew as the lead and including an MPH student. Objectives: Most HR HPV infections do not progress to cancer, but progression is associated with persistent infection. HPV was previously thought to "clear" or persist, but newer studies suggest that HPV may be a latent virus that can be re-detected episodically. This study examined the persistence and/or redetection of HR HPV in young women recruited 6 years after identification of a HR HPV infection during their prior involvement in a longitudinal study of adolescent women. Methods: 30 women from the prior study (the Young Women’s Project) were recruited for 2 visits, 6 weeks apart. During Visit 1 they had a Pap test, HPV DNA testing, HPV serology, and were administered a semi-structured interview. During Visit 2, Pap test results were given, a self-swab for HPV testing was obtained, and a qualitative interview was administered. Results: 15 women had normal Pap test results, 2 were ASCUS, and 3 LGSIL. 12 women had a history of colposcopy for a previous abnormal Pap results and 4 had received treatment for cervical dysplasia. 26 of the women had HPV 16 in the original YWP study. 11 had HPV 16 redetected in the present study, including in 6 women who had apparently "cleared" the infection during the original YWP study. Conclusions: High risk HPV may not always (or ever) "clear" Persistent low viral levels may not be detectible. However, some HPV infections may be episodically detected if changes in immune function lead to increases in viral copies. Questions raised by this research include: 1) who is at risk for episodic detection?; 2) what factors are predictive of episodic detection?; 3) how likely is episodically-detect HR HPV to progress to cervical disease?; 4) what is the predictive value of a negative HPV DNA test?; and 5) what do we tell women with a positive HR HPV DNA screen if they have been sexually abstinent or with a life-long partner ... or if they have a new partner?
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    Rapid Development of Clinical Trial Candidates Using Cancer Systems Pharmacology: a Lymphoma Case Study
    (Office of the Vice Chancellor for Research, 2015-04-17) Arkenberg, Matthew; Johnson, Kylee; Kaur, Palakpreet; Moors, Kelly; Weisman, Michael
    Due to intrinsic complex molecular interactions, the “one disease – one target – one drug” strategy for disease treatment is no longer the best option to treat complex diseases such as cancers. To assess drug pharmacological effects, we assume that “ideal” drugs for patients can treat or prevent the disease by modulating its gene expression profile to a similar level of those in healthy people. A drug that may not have been approved to treat a cancer yet, based on its gene expression target profile is the most successfully at modulating the gene expression to being of similar level to a healthy person is known as drug repurposing. The goal of this study was to develop an in silico framework which would determine which drug(s) could be repurposed to treat more complex disease of interest such as cancers. Using three subcategories of Non-Hodgkin’s Lymphoma (Burkitt’s, Mantle, Diffuse Large B-Cell) as case studies, manual curation was done to collect data on drug-protein interaction, drug similarity analysis based on structure and protein target, and curation; disease-protein interactions, and protein-protein interactions. A network will be created from the curated data known as a Pharmacology Effect Network (PEN). The Pharmacological Effect on Target (PET) algorithm will then be used to rank the curated drugs. This ranking will help determine which of the investigated drugs not currently used to treat one of the three subsets of Non-Hodgkin’s lymphoma could possibly be recommended to treat them. Although this project was primarily done using manual curation, the framework of each curated relationship used by each curator has been incorporated into a web interface. This webpage will allow for more automation of the curation process with little help from the curator and should improve the speed and accuracy of the curation process. Mentors: Jake Chen7, Xiaogang Wu7, Walter Jessen8 7IU Center for Systems Biology and Personalized Medicine, IUPUI; 8Informatics, Covance, Greenfield