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Biological Modulators of Experimental Cancer Therapy: Filamin-A and Mutations in DNA Repair Gene

Jingyin Yue
M.S, Peking Union Medical College-2002

Thesis Advisor: Zhiyuan Shen M.D., Ph. D.
Graduate Program Cellular & Molecular Pharmacology

CINJ Auditorium - A
New Brunswick

Friday, December 23, 2011
10:00 a.m.


Many chemotherapeutic drugs and radiation therapy are used to treat cancer due to their geno-toxicity to the cancer cells. The overall outcome of these treatments relies not only on the cancer cells response to DNA damage but also can be affected by normal tissue sensitivity to DNA damage. It is known that altered expression of many molecules can be used as biomarkers for optimization of individualized treatment design. Identification and characterization of these molecules that can modulate treatment outcomes remains a major task for cancer biologists. My thesis research contains two parts: 1) roles of filamin-A in cancer response to experimental therapy and metastasis, and 2) the identification of DNA repair gene mutations that are responsible for an individual sensitivity to therapeutic DNA damage.
My study shows that the cytoskeleton protein filamin-A plays a role in regulation of homologous recombination repair of DNA damage. Either natural loss or down-regulation of filamin-A can sensitize cancer cells to several DNA damage based experimental therapy. In addition, I found that filamin-A is required for cell migration. Filamin-A deficiency dramatically reduces metastases of cancer cells in mouse models, but also is associated with distant metastases in breast cancer patients. Therefore, filamin-A is a novel biological modulator for the outcomes of cancer treatment. To further understand the molecular mechanism of radiation sensitivity of normal tissues, I systematically analyzed the DNA damage response network in a radiation sensitive human fibroblast cell line. I identified two mutations in the LIG4 gene that are responsible for the hyper-sensitivity to radiation and other DNA damage agents.
In summary, my work established filamin-As roles in cancer sensitivity to therapeutic DNA damage and metastasis, and the filamin-A status in cancer cells may be used to optimize treatment design. In addition, a novel mutation in DNA ligase IV was found to be responsible for normal cell sensitivity to therapeutic DNA damage. These data conclude that filamin-A and a new mutation of DNA ligase IV are effective modulators for the outcomes of cancer therapy.

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