title: Fascin is a key regulator of breast cancer invasion that acts via the modification of metastasis-associated molecules.
abstract: The actin-bundling protein, fascin, is a member of the cytoskeletal protein family that has restricted expression in specialized normal cells. However, many studies have reported the induction of this protein in various transformed cells including breast cancer cells. While the role of fascin in the regulation of breast cancer cell migration has been previously shown, the underlying molecular mechanism remained poorly defined. We have used variety of immunological and functional assays to study whether fascin regulates breast cancer metastasis-associated molecules. In this report we found a direct relationship between fascin expression in breast cancer patients and; metastasis and shorter disease-free survival. Most importantly, in vitro interference with fascin expression by loss or gain of function demonstrates a central role for this protein in regulating the cell morphology, migration and invasion potential. Our results show that fascin regulation of invasion is mediated via modulating several metastasis-associated genes. We show for the first time that fascin down-regulates the expression and nuclear translocation of a key metastasis suppressor protein known as breast cancer metastasis suppressor-1 (BRMS1). In addition, fascin up-regulates NF-kappa B activity, which is essential for metastasis. Importantly, fascin up-regulates other proteins that are known to be critical for the execution of metastasis such as urokinase-type plasminogen activator (uPA) and the matrix metalloproteases (MMP)-2 and MMP-9. This study demonstrates that fascin expression in breast cancer cells establishes a gene expression profile consistent with metastatic tumors and offers a potential therapeutic intervention in metastatic breast cancer treatment through fascin targeting.
authors.affiliation: Stem Cell Therapy Program, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. MAlwan@kfshrc.edu.sa
authors.forename: Monther
authors.initials: M
authors.lastname: Al-Alwan
authors.forename: Safiah
authors.initials: S
authors.lastname: Olabi
authors.forename: Hazem
authors.initials: H
authors.lastname: Ghebeh
authors.forename: Eman
authors.initials: E
authors.lastname: Barhoush
authors.forename: Asma
authors.initials: A
authors.lastname: Tulbah
authors.forename: Taher
authors.initials: T
authors.lastname: Al-Tweigeri
authors.forename: Dahish
authors.initials: D
authors.lastname: Ajarim
authors.forename: Chaker
authors.initials: C
authors.lastname: Adra
mesh_terms: D000328:Adult; D017209:Apoptosis; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism; D014945:Wound Healing
chemical_list: C410024:BRMS1 protein, human; D002352:Carrier Proteins; C502658:FSCN1 protein, human; D008840:Microfilament Proteins; D016328:NF-kappa B; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; D014568:Urokinase-Type Plasminogen Activator; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9
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