Biology and Therapy of Breast Cancer Metastasis in the Brain and Bone in Nude Mice Lee Su Kim Department of Surgery, Hallym University, College of MedicinePhone No. : +82-31-380-3772Fax No. : +82-31-385-0157e-mail : firstname.lastname@example.orgBackground The majority of the death of women with breast cancer is the result ofmetastasis that are resistant to conventional therapies. Patients with breastcancer brain metastases cannot be cured and have a poor prognosis, despitedevelopment in diagnostic and therapeutic modalities. Especially, the highmortality rate from breast cancer metastasis has led to the intensive search formolecular alterations contributing to metastatic progression, with the aim ofdesigning targeted therapies. Several reasons account for the failure to treatmetastases. First, breast cancers are biologically heterogeneous and containsubpopulations of breast cancer cells with different angiogenic, invasive, andmetastatic properties. Second, the process of metastasis selects for a smallsubpopulation of cells that preexist within parental neoplasm. Third, andperhaps the greatest obstacle for therapy, is that the outcome of metastasisdepends on multiple interactions (‘cross-talk’) of metastatic cells withhomeostatic mechanisms which the breast cancer cells usurp. Most recent datademonstrate that the organ microenvironment can influence the growth,invasion, and response of metastases to chemotherapy. Therapy of metastasisshould therefore be targeted against both the metastatic tumor cells andhomeostatic factors that promote metastasis. Two sites where breast cancermetastases are commonly found are brain and bone. Breast cancer is the
second most common cause of brain metastasis, after lung cancer, with clinicaldiagnosis in 10 to 15% of patients, and found at autopsy in 20 to 30% ofpatients. Bone metastases are found in a higher percentage of patients, up to90% of women with metastatic breast cancer.Proposition in breast cancer research works to ColumbiaUniversity Department of Surgery Although it is well known that breast cancers can metastasize to the brain andbone, relatively little is known about how theses metastases form, and whatphenotypes are characteristic of breast cancers with the ability to grow in theseorgan environments. Without such information, the rational design of newtherapies to prevent or control the growth of metastases is impossible. In largepart, the progress in understanding the biology of breast cancer metastasis hasbeen limited by the lack of suitable cell lines and experimental models. We propose to develop experimental models, based on the nude mousemodels we have already established, to study the pathogenesis of breast cancermetastasis in the brain and bone. Especially, we propose to investigate howthese interactions between tumor cells and normal tissue environments affectthe development of metastases, using nude mouse models of human cancermetastasis, with a special focus on breast cancer. For the brain metastasismodel, we focus on the role of angiogenic factors, including VEGF, and use amodel of injection of tumor cells in the intra-carotid artery to simulatedissemination to the brain. For the bone metastasis model, we will analyze theexpression of osteolytic cytokine from bone metastasized tissue, and develop amodel of breast cancer bone metastasis, utilizing direct injection into mousetibia bone through knee joint and formation of bone metastases after systemicinjection. On the other hand, we propose to study the immunogenic characteristics ofbreast cancer and the design of effective immunotherapeutic modalities forsolid tumor, regional lymph node metastases, and visceral and CNS metastases.
Biographical Sketches M.D., Chung-Ang University College of Medicine (Seoul, Korea), 1985 M.S., Chung-Ang University College of Medicine (Seoul, Korea), 1992Diplomate, Surgery, Korean Surgical Society, 1993Ph.D., Chung-Ang University College of Medicine (Seoul, Korea), 1995Assistant Professor, Department of Surgery Hallym University College of Medicine, 1996 Associate Professor, Department of Surgery Hallym University College of Medicine, 2000 Postdoctoral fellow, UT M.D. Anderson Cancer Center (Houston, TX), 2000 – 2002 Selected Key Publications1. Dina Chelouche Lev, Lee Su Kim, Vladislava Melnikova, Maribelis Ruiz, Honnavara N. Ananthasswamy and Janet E. Price. Dual blockade of EGFR and ERK1/2 phosphorylation potentiates growth inhibition of breast cancer cells. Submitted for publication to Clinical Cancer Research.2. Lee Su Kim, Weixin Lu and Janet E. Price. Vascular endothelial growth factor expression promotes the growth of breast cancer brain metastases in nude mice. Submitted for publication to Cancer Research.3. Weixin Lu, Jindong Su, Lee Su Kim, Corazon D. Bucana, Cherrie Donawho, Junqing He, Isaiah J. Fidler, and Zhongyun Dong. Active
Specific Immunotherapy against occult brain metastasis. Submitted for publication to Cancer Research.4. Claudia Miller, Galina Kiriakova, Lee Su Kim, Kristin L. Weber and Janet E. Price. Characterization of a novel breast cancer cell line established from a bone metastasis. In preparation.5. Jin Hee Sohn, Lee Su Kim, Seoung Wan Chae, and Hyung Sik Shin. Fine needle aspiration cytologic findings of breast mucinous neoplasms. Differential diagnosis between mucocelelike tumor and mucinous carcinoma. Acta Cytologica 45(5) : 723-729, 20016. Lee Su Kim, Bae Jung Hun, Jung Jin Kim and Sung Kim. The effect of long-term tamoxifen therapy on endometrium evaluated by transvaginal sonography in postmenopausal women undergone breast cancer surgery. J Kor Cancer Assoc 32(3) : 539-544, 20007. Lim Min Gyun, Lee Su Kim, Dong Gun Kim and Sung Kim. Identification of Pseudomonas aeruginosa isolated from burn patients by Nested PCR based on outer membrane lipoprotein oprL gene. J Kor Burn Assoc 2(2) : 96-104, 19998. Lee Su Kim, Jin Hee Shon and Bong Hwa Lee. Correlation of breast cancer with atypical ductal hyperplasia on fine-needle aspiration cytology speciemens. J Kor Cancer Assoc 31(3) : 517-522, 19999. Jin Hee Shon and Lee Su Kim. Infiltrating duct carcinoma encountered in paraffin-injected breast. Plastic Reconstr Surg 102(5) : 1773-1774, 199810. Lee Su Kim, Gyun Dong Park, and Sung Kim. Prognostic significance of peritumoral lymphatic vessel invasion in breast cancer. J Kor Cancer Assoc 30(5) : 945-950, 199811. Lee Su Kim, Sung Kim and Bong Hwa Lee. Prognostic significance of tumor angiogenesis in breast cancer. J Kor Surg Soc 55(1) : 34-43, 199812. Dong Young Nho and Lee Su Kim. Germline mutation of BRCA2 gene in Korean breast/ovarian cancer families. J Kor Cancer Assoc 30(2) : 242-252, 1998