> 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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