Abstract 3290: A novel model of breast cancer metastasis: Killing two birds with one stone
Authors: Khotskaya Yekaterina B. , Shen Jia , Chang Shih-Shin , Yu Dihua , Steeg Patricia S. , Hung Mien-Chie 
Published: August 2012

American women carry a lifetime risk of 1:8 of developing breast cancer, with metastatic disease remaining incurable. Between 70-80% of breast cancer patients diagnosed with metastases will exhibit lesions in their skeleton and in 25% of patients bone is the first site of metastasis. Breast cancer bone metastases are most frequently osteolytic. Thus, patients exhibiting bone lesions might suffer from nerve compression, bone fractures, hypercalcemia, pain, or paralysis. Existing treatment strategies for patients with bone metastases are palliative and designed to limit cancer-associated bone loss. It has been difficult to study breast cancer dissemination to bone due to lack of good animal models and little biopsy tissue availability. For human xenografts to establish bone lesions, human breast cancer cells are injected into the left ventricle of the heart, a procedure technically challenging and not 100% efficient. Resulting bone lesions are slow to develop and may be easy to miss on x-ray examination. Here, we show that a well-described parental MDA-MB-231 breast cancer cell line recapitulates progression of human disease when injected intravenously through the lateral tail vein into athymic nude mice. For reasons yet unclear, 30-50% of animals develop rapid and extremely lytic bone lesions in lumbar, sacral and caudal vertebrae and hind limbs. Similar to breast cancer patients, these animals exhibit pathologic fractures and paralysis, necessitating euthanasia within 4 weeks after cell inoculation. Interestingly, animals not affected by bone metastases go on to develop overt lung metastases within 10-12 weeks after cell inoculation. Bioluminescence imaging studies indicated presence of luciferase-tagged MDA-MB-231 cells in lungs of all mice at 2 and 24 hours post-cell inoculation. Within three weeks post-injection, large lesions were detected in the lumbar to caudal vertebrae regions and hind limbs of mice injected with luciferase-tagged (6/15 mice) or parental MDA-MB-231 cells (7/13 mice). Bone osteolysis was confirmed by x-ray, and paralysis occurred as early as 3 weeks after cell injection. Cytogenetic “finger printing” preformed by the institutional core facility confirmed that cell lines used exhibit properties of MDA-MB-231 cells consistent with ATCC profile. Furthermore, molecular comparison of these cell lines with MDA-MB-231 cells obtained from other sources, including ATCC, revealed no differences. Unexpectedly, when examined in an orthotopic breast cancer model, MDA-MB-231 cells used in these studies produced rapidly growing tumors that spontaneously metastasized to lymph nodes and lungs, while MDA-MB-231 cells purchased from ATCC were completely non-tumorigenic. Studies are underway to determine a molecular mechanism responsible for this aggressive metastatic phenotype. This model may serve as a valuable tool for screening new therapeutics aimed to stop growth of metastases at multiple sites.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3290. doi:1538-7445.AM2012-3290