A histological analysis of the role of a LOX-PP variant in breast cancer, leukemia, and lymphoproliferative disease
Emmerling, Michael John
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BACKGROUND: In their lifetime, 42% of men and 38% of women will be diagnosed with cancer. One of the most prominent cancers in women is breast cancer, which represents 14.8% of newly diagnosed cancers. Research has demonstrated the importance of the lysyl oxidase (LOX) gene, more specifically the lysyl oxidase propeptide (LOX-PP), in the attenuation of breast cancer and in mouse xenograft models, making it an important and ongoing area of investigation. In recent, unpublished experiments, mice with a variant of LOX-PP were treated with 7,12-Dimethylbenz[a]anthracene (DMBA) to induce breast cancer. However, some of the treated mice developed poor body conditions without any signs of having developed breast cancer. Published studies have demonstrated that, following treatment with DMBA, some mice generate leukemia or other lymphoproliferative diseases. Research has shown that identification of these diseases is possible via histological analyses or immunohistochemistry. Objective: To determine the cause of poor body conditions in mice treated with DMBA that did not develop mammary tumors by histological analyses and immunohistochemistry. Additionally, to determine the difference between a variant of LOX-PP (LOX-PPv) knock-in (Ki) and wild type (WT) mice in the generation of poor body conditions or leukemia/lymphoproliferative disease. METHODS: A total of 48 mice, 24 LOX-PPv Ki and 24 WT, were treated with DMBA and observed for mammary tumor formation. Body conditions of the mice were observed and noted, and liver samples from these mice were obtained and analyzed via histological and immunohistochemistry interventions. In Hematoxylin & Eosin (H&E) assessments of mice livers, mice were classified as normal or as having possible lymphocyte infiltration, mild lymphocyte infiltration, or massive lymphocyte infiltration. Staining with the Ki-67 antibody in immunohistochemistry allowed for classification of mouse livers as normal or as having slightly positive or massively positive expression of the Ki-67 antigen. The degree to which each liver sample was positive for both readings was compared and further analyzed. RESULTS: A total of 9 mice (30.4% of Ki mice and 8.7% of WT mice) displayed poor body conditions following DMBA treatment. Of the 9 (7 Ki and 2 WT) mice having poor body condition, 2 Ki mice suffered from severe dermatitis. For the 7 remaining mice, no cause for such poor body conditions was obvious. 6 of these mice (85.7%) were diagnosed with leukemia. In all other DMBA-treated mice, 52.6% of Ki and 23.8% of WT displayed some degree of abnormal lymphocyte infiltration in the liver, while a total of 39.1% of the K¬I mice and 69.6% of the WT mice had normal liver histologies. 60.9% of Ki and 45.5% of WT mice displayed some degree of positivity for expression of Ki-67. CONCLUSIONS: Mice not diagnosed with breast cancer but that were suffering from poor body conditions likely had developed leukemia or some other lymphoproliferative disease. In the mice not definitively diagnosed with leukemia by a pathologist, H&E analyses and immunohistochemistry of the livers showed lymphocyte infiltration and cellular proliferation possibly indicative of leukemia., but further tests are necessary to confirm this. Furthermore, LOX-PPv Ki mice appeared to have a greater likelihood of generating poor body conditions or some observable sign of abnormal lymphocyte infiltration in the liver versus their WT counterparts when treated with DMBA.