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Autophagy and mammary physiology: Role of autophagy in mammary homeostasis and tumorigenesis

by
Fred Lozy
B.S. Rutgers University - May 2007



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

Rutgers Cancer Institute of New Jersey
195 Little Albany Street
Auditorium A
New Brunswick

Thursday, August 1, 2013
2:30 p.m.


Abstract

Autophagy is an evolutionarily conserved catabolic process essential for cellular homeostasis. Normally, autophagy is induced to maintain viability in response to cellular stressors and defective autophagy has been associated with many human pathologies, such as neurodegeneration, inflammatory disease, and cancer. Elucidating the complex role of autophagy in different biological contexts may reveal vital information leading to the prevention or better treatment of these diseases, specifically cancer in our case.

The autophagy regulator Beclin1 (BECN1) is allelically deleted in human breast, ovarian, and prostate cancers and Becn1+/- mice are tumor-prone. At the same time, however, human tumors also induce autophagy in response to stress and chemotherapy. Nonetheless, the functional status of autophagy in tumors has remained difficult to evaluate. We performed gene expression microarray analysis on Becn1+/+ and Becn1+/- iMMECs and their resultant allograft tumors in nude mice to identify biomarkers of defective autophagy. Our gene expression data revealed an upregulation of epithelial keratins in autophagy-defective Becn1+/- iMMECs and mammary tumors. We also discovered that phospho-K8 accumulates in metabolically stressed autophagy-deficient iMMECs and their resultant tumors and in Atg-deficient mammary glands. Phospho-K8 accumulation also correlates with low BECN1 protein levels in human breast tumors, indicating that it may be a marker for defective autophagy.

Gene expression analysis was useful to uncover the role of ATG proteins in mammary involution. Analysis of publicly available microarray data of mouse mammary development and subsequent qRT-PCR of wild type and Atg-deficient involuting mouse mammary glands revealed upregulation of autophagy regulators in the first 24 hours of involution in wild type glands, but impairment in induction of these genes in Atg- glands. Furthermore, we discovered that Atg-deficient mammary epithelial cells are defective in dead cell phagocytosis, which results in transient delay in involution and abnormal persistence of involution-associated inflammation.

Additionally, we discovered that low BECN1 expression correlates with HER2-positive and basal-like breast cancer. HER2 was found to inhibit stress-induced autophagy regardless of Becn1 status. Crossing Becn1+/- mice to the MMTV-neu and MMTV-PyMT mouse mammary tumor models yielded no change in their mammary tumorigenesis, indicating that Becn1 deletion is not a driver mutation in HER2-associated breast cancer.


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