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April 2013

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From:
"Diane St. Germain" <[log in to unmask]>
Date:
Fri, 5 Apr 2013 16:56:16 -0400
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To: Biosciences Graduate Students <[log in to unmask]>, BINF Students <[log in to unmask]>, SSB Faculty <[log in to unmask]>, Robin Couch <[log in to unmask]>, Calvin B Carpenter <[log in to unmask]> cc: Jennifer Bazaz <[log in to unmask]>
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> Dissertation Defense Announcement
> To:  The George Mason University Community
>
> *Candidate: Virginia Espina
> Program:    PhD Biosciences*
>
> *Date:   Friday April 19, 2013
> Time:   2:30 p.m.
> Place:  George Mason University
>             Fairfax Campus 
> <http://www.gmu.edu/resources/welcome/Directions-to-GMU.html>
>             **Research Hall, Room 161**  
> * 
> Committee Chair: Dr. Lance Liotta
> Committee members: Dr. Calvin Carpenter, Dr. Robin Couch, Dr. Kirsten 
> Edmiston, Dr. Brian D. Mariani
>
> *Title: "Killing Pre-Invasive Breast Cancer by Targeting Autophagy: A 
> New Vision for Chemoprevention"*
>
> The dissertation is on reserve in the Johnson Center Library, Fairfax 
> campus.
> The doctoral project will not be read at the meeting, but should be 
> read in advance.
>
> All members of the George Mason University community are invited to 
> attend.
>
>
> *ABSTRACT:*
> All invasive breast cancer is thought to be preceded by a pre-invasive 
> state in which cells accumulate within the breast ductal niche. Breast 
> cancer progression is thought to be a multi-step process involving a 
> continuum of changes from a normal phenotype through hyperplastic 
> lesions, carcinoma in situ, invasive carcinoma, to metastatic disease. 
> Previously it was assumed that the invasive phenotype acquired major 
> genetic changes during the phenotypic transition from ductal carcinoma 
> in situ (DCIS) to invasive carcinoma. In direct contradiction to this 
> previous assumption, herein we demonstrate, for the first time, the 
> pre-existence of genetically abnormal, tumorigenic carcinoma 
> progenitor cells within human breast DCIS lesions.
> Human DCIS cells were cultivated ex vivo without a priori enzymatic 
> treatment or sorting. The DCIS organoid cultures induced the emergence 
> of neoplastic epithelial cells exhibiting the following 
> characteristics: a) spontaneous generation of hundreds of spheroids 
> and duct-like 3-D structures in culture within 2-4 weeks, b) 
> tumorigenicity in NOD/SCID mice, and c) in vitro migration and 
> invasion of autologous breast stroma. Proteomic characterization 
> revealed that DCIS cells up-regulate signaling pathways directly, and 
> indirectly, linked to cellular autophagy. Cells that proliferate and 
> accumulate within the non-vascular intraductal space are under severe 
> hypoxic and metabolic stress. Pre-invasive cells must adapt to hypoxic 
> stress within the duct in order to survive and proliferate. Autophagy 
> was found to be required for survival and anchorage independent 
> growth, in the patient's original DCIS lesion and the mouse xenograft. 
> Molecular karyotyping demonstrated DCIS cells to be cytogenetically 
> abnormal (copy number loss or gain in chromosomes including 1, 5, 6, 
> 8, 13, 17) compared to the normal karyotype of the non-neoplastic 
> cells in the patient's breast tissue.
> To demonstrate the dependence of the cytogenetically abnormal DCIS 
> cells on autophagy as a survival mechanism, primary human DCIS cell 
> cultures were treated with chloroquine phosphate, a lysosomotropic 
> inhibitor of autophagy. Chloroquine treatment completely suppressed 
> the generation of DCIS spheroids/3-D structures, suppressed ex vivo 
> invasion of autologous stroma, induced apoptosis, suppressed autophagy 
> associated proteins including Atg5, AKT/PI3 Kinase, and mTOR, 
> eliminated cytogenetically abnormal spheroid forming cells from the 
> organ culture, and abrogated xenograft tumor formation.
> With the broad goal of arresting all breast cancer at the 
> non-invasive, non-lethal stage, a phase I/II clinical trial (PINC; 
> Preventing Invasive breast Neoplasia with Chloroquine) was established 
> for clinical evaluation of the safety and efficacy of chloroquine 
> phosphate as a strategy to treat human breast Ductal Carcinoma in Situ 
> (DCIS). Therapy that induces regression, or prevents progression, of 
> occult or overt pre-invasive lesions could comprise a new treatment 
> strategy for pre-invasive cancers independent of hormone receptor status.
>
>
>  ### 


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