Flotillin-2 deficiency leads to reduced lung metastases in a mouse breast cancer model.

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.

• Authors: T Berger, T Ueda, E Arpaia, I I C Chio, E A Shirdel, I Jurisica, K Hamada, A You-Ten, J Haight, A Wakeham, C C Cheung, T W Mak
• Journal: Oncogene (Oncogene) Vol. 32 Issue 41 Pg. 4989-94 (Oct 10 2013) ISSN: 1476-5594 [Electronic] England
• PMID: 23146906 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Membrane Proteins
• flotillins

Topics

• Animals
• Cell Line, Tumor
• Cell Transformation, Neoplastic
• Comparative Genomic Hybridization
• Disease Models, Animal
• Female
• Gene Silencing
• Humans
• Lung Neoplasms (genetics, secondary)
• Mammary Neoplasms, Experimental (pathology)
• Membrane Proteins (deficiency, genetics)
• Mice