title: Profilin-1 downregulation has contrasting effects on early vs late steps of breast cancer metastasis.
abstract: Profilin1 (Pfn1), a ubiquitously expressed actin-binding protein, has an indispensable role in migration and proliferation of normal cells. Seemingly contrary to its essential cellular functions, Pfn1's expression is downregulated in breast cancer, the significance of which is unclear. In this study, expression profiling of Pfn1 in human breast cancer specimens correlates lower Pfn1 expression levels with propensity to metastasize. Xenograft experiments further establish a causal relationship between loss of Pfn1 expression and increased dissemination of breast cancer cells (BCCs) from the primary mammary tumor. BCCs exhibit a hyperinvasive phenotype (marked by matrix metalloproteinase-9 upregulation, faster invasion through collagen matrix) and acquire increased proficiency to transmigrate through endothelial barrier (an obligatory step for vascular dissemination) when Pfn1 expression is suppressed. In Pfn1-deficient cells, hyperinvasiveness involves a phosphatidylinositol 3-kinase-PI(3,4)P2 signaling axis while augmented transendothelial migration occurs in a vascular endothelial growth factor-dependent manner. Contrasting these dissemination promoting activities, loss of Pfn1, however, dramatically inhibits metastatic outgrowth of disseminated BCCs, suggesting that Pfn1 has a key role in the metastatic colonization process. In summary, this study shows that Pfn1 has a dichotomous role in early vs late steps of breast cancer metastasis.
authors.affiliation: Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Ding
authors.affiliation: Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Joy
authors.affiliation: 1] Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA [2] Magee Women's Hospital, Pittsburgh, Pittsburgh, PA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Bhargava
authors.affiliation: Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Gunsaulus
authors.affiliation: Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: N
authors.initials: N
authors.lastname: Lakshman
authors.affiliation: Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: M
authors.initials: M
authors.lastname: Miron-Mendoza
authors.affiliation: Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: M
authors.initials: M
authors.lastname: Petroll
authors.affiliation: Department of Cell Biology and Anatomy, Albert Einstein College of Medicine, New York, NY, USA.
authors.forename: J
authors.initials: J
authors.lastname: Condeelis
authors.affiliation: 1] Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA [2] Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA [3] McGowan Institute of Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Wells
authors.affiliation: 1] Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA [2] Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA [3] McGowan Institute of Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA [4] Magee Women's Research Institute, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: P
authors.initials: P
authors.lastname: Roy
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism; D051304:Profilins / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D013997:Time Factors; D046888:Tissue Array Analysis; D057705:Transendothelial and Transepithelial Migration / Q000235:genetics; D014183:Transplantation, Heterologous
chemical_list: D010716:Phosphatidylinositols; D051304:Profilins; C118301:phosphoinositide-3,4-bisphosphate; D019869:Phosphatidylinositol 3-Kinases; D020780:Matrix Metalloproteinase 9