Pilot Project F: Inhibiting the Angeiogenesis in Breast Tumors by Inducing Unfolded Protein Response - Testing a New Paradigm
Co-Investigators
Dipak Banerjee, Ph.D., Professor, Department of Biochemistry, University of Puerto Rico-Medical Sciences Campus, Rio Piedras, Puerto Rico
Sen Pathak, Ph.D., Professor, Cancer Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas
Mien-Chie Hung, Ph.D., Professor, Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
Outcomes from this study will enhance the understanding of how TM-induced down-regulation of LLO leads to UPR-mediated apoptotic death of tumor microvasculature. This study will also help in developing new generation anti-angiogenic therapeutics to eliminate breast cancer.
Specific Aims
- To test the hypothesis that TM-mediated "ER stress" arrests capillary endothelial cells in G1 and activates an apoptotic pathway by altering regulation of apoptotic signals due to differential expression of pro- and anti-apoptotic family of genes/ gene products (months 1-36)
Working hypothesis: Cell cycle arrest at G1 is initiated by DNA damage that occurs because of accumulation of unfolded glycoproteins by cytokine mimic TM. Such injury inappropriately stimulates formation of cross talk between cell cycle regulators. - To test the hypothesis that TMm-induced "ER stress" alters telomere dynamics and induces severe chromosomal instability (months 1-36)
Working hypothesis: TM inhibits telomerase activity and makes telomere dysfunctional by reducing T2AG3 repeats. - To test the hypothesis that TMm-induced "ER stress" limits the intratumoral microvascular density in breast carcinoma in athymic nude mice xenografts with estrogen receptor-positive (Er+) and estrogen receptor-negative (Er-) breast cancer cells (months 1-36)
Working hypothesis: TM acts to eliminate the breast cancer in athymic nude mice.