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- Title
Flotillin-2 deficiency leads to reduced lung metastases in a mouse breast cancer model.
- Authors
Berger, T; Ueda, T; Arpaia, E; Chio, I I C; Shirdel, E A; Jurisica, I; Hamada, K; You-Ten, A; Haight, J; Wakeham, A; Cheung, C C; Mak, T W
- Abstract
Flotillin microdomains, specialized lipid raft domains in cell membranes, serve as physical platforms for many different molecules important in crucial intracellular signaling pathways. Flotillin-2 (Flot2), together with flotillin-1, is a marker for lipid raft microdomains distinct from caveolar lipid rafts, and has been implicated in the progression of cancer and metastasis formation. Based largely on studies in xenograft models, flotillin-2 has been implicated in the progression of multiple types of human tumors, including breast cancer. In our studies, we identified flotillin-2 as highly amplified in a high-throughput comparative genomic hybridization screen of human breast cancer cell lines and breast tumor samples. Short hairpin RNA-mediated reduction of flotillin-2 protein levels significantly reduced the tumorigenicity and metastatic capability of a human breast cancer cell line in vivo. We generated mice deficient for flotillin-2 and also found a reduction of flotillin-1 protein levels and complete absence of flotillin-specific membrane microdomains in these mice. To examine the role of Flot2 in mammary tumorigenesis and lung metastasis, we used an in vivo molecular genetics approach, crossing a well-characterized transgenic mouse model of breast cancer, the MMTV-PyMT (mouse mammary tumor virus-polyoma middle T antigen) mouse, with gene-targeted Flot2−/− mice. Flotillin-2 deficiency lead to a striking reduction in the number of lung metastasis observed, but had no influence on primary tumor formation in this model. Our results indicate, using a novel in vivo animal model approach, that Flot2 is an important regulator of mammary tumor-derived lung metastasis.
- Subjects
MEMBRANE proteins; LUNG cancer; PROTEIN deficiency; BREAST cancer; LABORATORY mice; TUMOR markers; NEOPLASTIC cell transformation; FLOTILLINS
- Publication
Oncogene, 2013, Vol 32, Issue 41, p4989
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/onc.2012.499