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Monoallelic BECN1 drives immature mammary epithelial cell expansion and promotes WNT-driven mammary tumorigenesis

by
Michelle Turek Cicchini
B.S., University of Maryland - 2009


Thesis Advisor: Vassiliki Karantza, M.D., Ph.D.
Graduate Program in Cellular & Developmental Biology

Rutgers Cancer Institute of New Jersey
Auditorium B
New Brunswick

Wednesday, December 18, 2013
10:00 a.m.


Abstract

Beclin1 (BECN1) is an essential regulator of the evolutionarily conserved process of autophagy, which maintains cell homeostasis and survival by targeting cytoplasmic material and organelles to lysosomes for degradation. BECN1 defects have been implicated in breast cancer, as BECN1 is found to be allelically deleted in human breast tumors and Becn1+/- mice develop mammary hyperplasias. Additionally, low BECN1 mRNA levels correlate with the HER2 and Triple-Negative breast cancer subtypes. Other studies have shown Becn1+/- immortalized mouse mammary epithelial cells (iMMECs) to be more sensitive to metabolic stress, leading to increased DNA damage, genomic instability, and promoting tumorigenesis in an apoptosis-defective background.

Systematic examination of mammary glands (MGs) from Becn1+/- mice revealed increased ductal branching in puberty and development of mammary hyperplasias in association with accumulation of keratin 6 (K6)-positive mammary epithelial cells, functional enrichment in mammary stem and progenitor cells, and aberrant expression of the Receptor Activator of NFB Ligand (RANKL), which have all been implicated in mammary tumorigenesis. In support of our hypothesis that stem/progenitor cell expansion in MGs from Becn1+/- mice increases the number of transformation-susceptible cells, we found that, Becn1+/- female mice developed parity-associated mammary tumors. Furthermore, monoallelic Becn1 loss accelerated mammary tumorigenesis in MMTV-Wnt1 mice and resulted in tumors with basal-like characteristics and RANK-pathway activation.

Our results our clinically relevant, as human breast cancers with low BECN1 expression and activated WNT signaling have poor prognosis, are primarily triple-negative tumors characterized by basal cell markers, upregulation of embryonic cell and RANK/NFB pathway gene signatures. We have, thus, identified specific contexts, i.e. parity and activated WNT signaling, in which Becn1 heterozygocity promotes mammary tumorigenesis and we have generated novel mouse models for studying the pathophysiology and treatment of parity-associated breast cancer and a clinically aggressive triple-negative breast cancer (TNBC) subtype.


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