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Role of Autophagy in Mammary and Pancreatic Tumorigenesis

Sameera Kongara
B.A., Rutgers University - 2007

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

Rutgers Cancer Institute of New Jersey
Auditorium B
New Brunswick

Monday, February 24, 2014


Autophagy, a recycling mechanism that targets proteins and organelles to lyososomes for degradation, is a stress inducible process that promotes cell survival. Allelic loss of the essential autophagy regulator, Beclin1, is frequently observed in breast tumors, and Beclin1+/- mice develop mammary gland hyperplasias. Previous studies from our lab utilizing immortalized mouse mammary epithelial cells (iMMECs) established that autophagy mitigates susceptibility to metabolic stress and prevents tumorigenesis by preserving genomic integrity. We extended our findings, and demonstrate that autophagy-deficiency is associated with increased oxidative and ER stress, and accumulation of p62 and keratins in iMMECs, iMMEC-derived tumors, and native mammary glands. Notably, increased Phospho(S73)-K8 expression, a stress marker, was detected in these autophagy-deficient tissues, and in human breast tumors expressing low levels of Beclin1, suggesting that it may be a useful surrogate for autophagy-deficient status.
In a separate study, we investigated novel therapies for pancreatic cancer treatment based on rational design. mTOR inhibitors have been unsuccessful in the treatment of pancreatic cancer, although aberrant activation of this pathway occurs frequently in this disease. Activation of autophagy is associated with resistance to mTOR inhibition, and recent studies have shown that autophagy facilitates pancreatic tumor growth. Therefore, we examined the therapeutic efficacy of combining mTOR and autophagy inhibition for the treatment of pancreatic cancers. Although our in vitro studies revealed that inhibiting autophagy sensitized human pancreatic cancer cells to the mTOR inhibitors, CCI-779 and RAD-001, we failed to detect this effect in vivo, with the autophagy inhibitor, chloroquine. Since chloroquine concentrations achieved in vivo may be insufficient to inhibit autophagy, we utilized U1 adaptor technology to attenuate Beclin1 expression and inhibit autophagy in vivo. Beclin1 U1 adaptors reduced the growth of pancreatic xenografts, which was associated with increased accumulation of mitochondria. Combined treatment with RAD-001 and Beclin1 U1 adaptor, however, was similar to RAD-001 treatment alone, possibly due to the diminished delivery of the adaptor to the tumor as a consequence of the anti-angiogenic effect of RAD-001. In summary, our work presents a novel method to inhibit autophagy in vivo, and demonstrates that autophagy inhibition in a mature tumor can be therapeutically beneficial.

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