Development of a breast cancer brain metastases model to study 131I radioablative therapy.
Authors: C Renier, A De, L Hou, J Dunkel, A Sun, T Prugpichailers, SS Gambhir, V Tse, IL Wapnir
Journal: Cancer Research (2009)

Abstract Abstract #2011 Background: An increasing number of women develop brain metastases (BM) after breast cancer (BC) treatment. A large proportion of these are estrogen/progesterone receptor-negative (ER-/PR-) and/or Her-2/neu overexpressing tumors. 131I radioablative therapy may provide a therapeutic alternative to treat metastases at this anatomic sanctuary since over 70% of invasive breast cancers, including a majority of ER- tumors and some brain metastases (unpublished data) express the sodium-iodide symporter (NIS). This approach relies on the success of radioiodide as a targeted treatment for thyroid cancers. To test this concept, we developed a BC BM model using tumor cells engineered to express NIS.&amp;#x2028; Methods: MDAMB231 and SKBr3 cell lines were transduced with a lentiviral vector carrying a bicistronic cassette with NIS and the firefly luciferase (Fluc) genes separated by an internal ribosomal entry site. Single cell clones were selected and characterized for iodide uptake and bioluminescence. NIS-Fluc-MDAMB231 or NIS-Fluc SKBr3 cells (2.5 x 106 cells) were implanted subcutaneously (sc) in the mammary fat pad (mfp) of nude mice (NCr nude; 5-6 weeks old; n=5). NIS-Fluc mfp tumor xenografts were then explanted, 1x1 mm pieces excised and inserted stereotactically into the basal ganglia of the animal. All tumor development was monitored by serial in vivo bioluminescent imaging. Once established, brain tumors were excised, dissociated, established in tissue culture and re-implanted sc in the mfp of a new set of mice. Successive passages in the mfp then in the brain were performed in an attempt to increase tumor take. A second strategy tested with MDAMB231 cells consisted of direct implantation of cells into the basal ganglia. NIS expression was evaluated on tissue sections with a polyclonal antibody raised against the C-terminus of the human NIS.&amp;#x2028; Results: All mice survived and were healthy in appearance. Intracranial implantation of mfp xenografts was highly successful with 66% take in both MDAMB231 (after two passages) and SKBr3 (after first passage). Bioluminescent imaging revealed sustained growth of tumors for more than 4 weeks. Microscopically, the explanted brain tumors had a cellular appearance without stromal cell or lymphocytic infiltration and were congruent with the histology of mfp xenografts. However, the tumor cell population was heterogeneous as NIS expression was present with plasma membrane staining in about 50% of SKBr3 and 15% of MDAMB231 cells. Direct cell implantations failed as no discernible bioluminescence was noted over a period of 3 weeks and no visible tumor at necropsy.&amp;#x2028; Conclusions: A BCBM model has been developed by implanting intracranially mfp xenografts obtained with ER-/PR- +/- Her-2/neu overexpressing cells. Using this model, it will be possible to evaluate the effects of 131I on NIS-expressing BCBM. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2011.