title: 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.affiliation: The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, ON, Canada.
authors.forename: T
authors.initials: T
authors.lastname: Berger
authors.forename: T
authors.initials: T
authors.lastname: Ueda
authors.forename: E
authors.initials: E
authors.lastname: Arpaia
authors.forename: I I C
authors.initials: II
authors.lastname: Chio
authors.forename: E A
authors.initials: EA
authors.lastname: Shirdel
authors.forename: I
authors.initials: I
authors.lastname: Jurisica
authors.forename: K
authors.initials: K
authors.lastname: Hamada
authors.forename: A
authors.initials: A
authors.lastname: You-Ten
authors.forename: J
authors.initials: J
authors.lastname: Haight
authors.forename: A
authors.initials: A
authors.lastname: Wakeham
authors.forename: C C
authors.initials: CC
authors.lastname: Cheung
authors.forename: T W
authors.initials: TW
authors.lastname: Mak
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D055028:Comparative Genomic Hybridization; D004195:Disease Models, Animal; D005260:Female; D020868:Gene Silencing; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000556:secondary*; D008325:Mammary Neoplasms, Experimental / Q000473:pathology*; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics*; D051379:Mice
chemical_list: D008565:Membrane Proteins; C106354:flotillins