title: Endophilin A2 Promotes TNBC Cell Invasion and Tumor Metastasis.
abstract: Triple-negative breast cancers (TNBCs) are highly aggressive cancers that lack targeted therapies. However, EGFR is frequently activated in a subset of TNBCs and represents a viable clinical target. Because the endocytic adaptor protein Endophilin A2 (SH3GL1/Endo II) has been implicated in EGFR internalization, we investigated Endo II expression and function in human TNBCs. Endo II expression was high in several TNBC cells compared with normal breast epithelial cells. Stable knockdown (KD) of Endo II was achieved in two TNBC cell lines, and although cell viability was unaffected, defects in receptor-mediated endocytosis were observed. EGFR signaling to Erk and Akt kinases was impaired in Endo II KD cells, and this correlated with reduced rates of EGFR internalization and cell motility. Endo II KD cells also displayed defects in three dimensional (3D) cell invasion, and this correlated with impaired extracellular matrix degradation and internalization of MT1-MMP. Endo II silencing also caused a significant reduction in TNBC tumor growth and lung metastasis in mammary orthotopic tumor xenograft assays. In human breast tumor specimens, Endo II expression was highest in TNBC tumors compared with other subtypes, and at the level of gene expression, high Endo II was associated with reduced relapse-free survival in patients with basal-like breast cancers. Together, these results identify a positive role for Endo II in TNBC tumor metastasis and a potential link with poor prognosis.
  
  
  CONCLUSIONS
  Endophilin A2 and related adaptor proteins represent important signaling hubs to target in metastatic cancers.
authors.affiliation: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada. Cancer Biology and Genetics Division, Queen's Cancer Research Institute, Kingston, Ontario, Canada.
authors.forename: Tomas
authors.initials: T
authors.lastname: Baldassarre
authors.affiliation: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada. Cancer Biology and Genetics Division, Queen's Cancer Research Institute, Kingston, Ontario, Canada.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Watt
authors.affiliation: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada. Cancer Biology and Genetics Division, Queen's Cancer Research Institute, Kingston, Ontario, Canada.
authors.forename: Peter
authors.initials: P
authors.lastname: Truesdell
authors.affiliation: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada. Cancer Biology and Genetics Division, Queen's Cancer Research Institute, Kingston, Ontario, Canada.
authors.forename: Jalna
authors.initials: J
authors.lastname: Meens
authors.affiliation: Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Schneider
authors.affiliation: Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada.
authors.forename: Sandip K
authors.initials: SK
authors.lastname: Sengupta
authors.affiliation: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada. Cancer Biology and Genetics Division, Queen's Cancer Research Institute, Kingston, Ontario, Canada. ac15@queensu.ca.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Craig
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism*; D008175:Lung Neoplasms / Q000556:secondary*; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness; D015398:Signal Transduction; D064726:Triple Negative Breast Neoplasms / Q000473:pathology*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C105159:SH3GL1 protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors