Vassiliki Karantza-Wadsworth Assistant Professor UMDNJ-RWJMS Department of Medicine The Cancer Institute of NJ, Rm. 3550 195 Little Albany Street New Brunswick. NJ 08901 (732) 235-8617 FAX - 6797 karantva@umdnj.edu

Breast cancer progression and treatment, autophagy, apoptosis, beclin1

Autophagy is an evolutionarily conserved catabolic process involving self-digestion of cellular organelles during starvation as a means of cell survival; however, if it proceeds to completion, autophagy can lead to cell death. The essential autophagy regulator beclin1 is monoallelically deleted in many breast cancers, but the mechanism of tumor suppression by autophagy has been unknown.

We have been studying the role of autophagy in mammary tumorigenesis by using a novel mouse mammary epithelial cell model. We recently found that autophagy mitigates metabolic stress and protects mammary cancer cells from genome damage and instability, likely thereby limiting tumorigenesis. We will further characterize the role of autophagy in breast cancer progression and treatment by: 1) determining the mechanism by which deficient autophagy promotes genome damage in mouse mammary epithelial cells and validating the identified mechanism in human breast cancer cell lines and tumors. The hypothesis is that autophagy defects compromise cellular metabolism under starvation resulting in DNA and likely also protein damage. DNA strand breaks and damaged protein accumulation will be compared in wild type and autophagy-deficient cells under metabolic stress in vitro and in tumors in vivo, and their underlying causes will be examined, 2) determining the role of deficient autophagy in breast cancer progression. The hypothesis is that autophagy defects promote genomic instability and synergize with breast cancer promoting functions to accelerate cancer progression. To test this hypothesis, tumors generated by autophagy-deficient cells will be tested for genomic instability and activation of breast cancer promoting biological pathways. Also, beclin1+/- mice will be crossed with mammary tumor-prone mice and mammary tumorigenesis will be studied, and 3) determining whether deficient autophagy correlates with disease stage, treatment responsiveness and clinical outcome in breast cancer by using human breast cancer databases.

The long-term objective of our scientific endeavors is to apply the knowledge obtained from basic research to the rational design of more efficacious treatments against breast cancer based on the functional status of important biological processes, such as autophagy.

Selected Publications

Bray K, Chen HY, Karp CM, May M, Ganesan S, Karantza-Wadsworth V, DiPaola RS, White E. (2009) Bcl-2 modulation to activate apoptosis in prostate cancer. Mol Cancer Res. 7(9):1487-96.

Mathew R, Karp CM, Beaudoin B, Vuong N, Chen G, Chen HY, Bray K, Reddy A, Bhanot G, Gelinas C, Dipaola RS, Karantza-Wadsworth V, White E. (2009) Autophagy suppresses tumorigenesis through elimination of p62. Cell. 137(6):1062-75.

Mathew R, Karantza-Wadsworth V, White E. (2009) Assessing metabolic stress and autophagy status in epithelial tumors. Methods Enzymol. 453:53-81.

Chen N, Karantza-Wadsworth V. (2009) Role and regulation of autophagy in cancer. Biochim Biophys Acta. 1793(9):1516-23.

Karantza-Wadsworth V, White E. (2008) A mouse mammary epithelial cell model to identify molecular mechanisms regulating breast cancer progression. Methods Enzymol. 446:61-76.

Karantza-Wadsworth V. (2008) AACR Annual Meeting: Autophagy in the forefront of cancer research. Autophagy. 4(5):731-3.

Karp CM, Tan TT, Mathew R, Nelson D, Mukherjee C, Degenhardt K, Karantza-Wadsworth V, White E. (2008) Role of the polarity determinant crumbs in suppressing Mammalian epithelial tumor progression. Cancer Res. 68(11):4105-15.

Mathew, R., Karantza-Wadsworth, V., and White, E. (2007) Role of autophagy in cancer. Nature Rev. Cancer 7(12):961-7.

Karantza-Wadsworth, V., and White, E. (2007) Role of autophagy in breast cancer. Autophagy 3, e1.

Karantza-Wadsworth, V., Patel, S., Kravchuk, O., Chen, G., Mathew, R., Jin, S., and White, E. (2007) Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis. Genes & Dev. 21:1621-1635.

Huang, C.-C., Karantza-Wadsworth, V., Vogel, B. E., Hutter, H., Kao, G., Chisholm, A. D., Hall, D. H., Yurchenco, P. D., and Wadsworth, W. G. (2003) Laminin Alpha subunits of C. elegans are required for assembly of specialized basement membranes. Development 130: 3343-58.