title: mDia1 regulates breast cancer invasion by controlling membrane type 1-matrix metalloproteinase localization.
abstract: Mammalian diaphanous-related formin 1 (mDia1) expression has been linked with progression of malignant cancers in various tissues. However, the precise molecular mechanism underlying mDia1-mediated invasion in cancer cells has not been fully elucidated. In this study, we found that mDia1 is upregulated in invasive breast cancer cells. Knockdown of mDia1 in invasive breast cancer profoundly reduced invasive activity by controlling cellular localization of membrane type 1-matrix metalloproteinase (MT1-MMP) through interaction with microtubule tracks. Gene silencing and ectopic expression of the active form of mDia1 showed that mDia1 plays a key role in the intracellular trafficking of MT1-MMP to the plasma membrane through microtubules. We also demonstrated that highly invasive breast cancer cells possessed invasive activity in a 3D culture system, which was significantly reduced upon silencing mDia1 or MT1-MMP. Furthermore, mDia1-deficient cells cultured in 3D matrix showed impaired expression of the cancer stem cell marker genes, CD44 and CD133. Collectively, our findings suggest that regulation of cellular trafficking and microtubule-mediated localization of MT1-MMP by mDia1 is likely important in breast cancer invasion through the expression of cancer stem cell genes.
authors.affiliation: Department of Life Science, Chung-Ang University, Seoul 06974, Korea.
authors.forename: Daehwan
authors.initials: D
authors.lastname: Kim
authors.affiliation: Department of Life Science, Chung-Ang University, Seoul 06974, Korea.
authors.forename: Jangho
authors.initials: J
authors.lastname: Jung
authors.affiliation: Department of Life Science, Chung-Ang University, Seoul 06974, Korea.
authors.forename: Eunae
authors.initials: E
authors.lastname: You
authors.affiliation: Department of Life Science, Chung-Ang University, Seoul 06974, Korea.
authors.forename: Panseon
authors.initials: P
authors.lastname: Ko
authors.affiliation: Department of Life Science, Chung-Ang University, Seoul 06974, Korea.
authors.forename: Somi
authors.initials: S
authors.lastname: Oh
authors.affiliation: Department of Life Science, Chung-Ang University, Seoul 06974, Korea.
authors.forename: Sangmyung
authors.initials: S
authors.lastname: Rhee
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D005260:Female; D000080865:Formins; D006801:Humans; D061986:MCF-7 Cells; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism; D009361:Neoplasm Invasiveness; D014162:Transfection
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C108962:DIAPH1 protein, human; D000080865:Formins; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14
keywords: breast cancer cells; invasion; mDia1; membrane type 1-matrix metalloproteinase (MT1-MMP); microtubule dynamics