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PLEASE NOTE the correct start time is 12:30 pm
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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:   12:30 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.
>>
>>
>>  ###