title: CAF-secreted IGFBPs regulate breast cancer cell anoikis.
abstract: Carcinoma-associated fibroblasts (CAFs) are now widely appreciated for their contributions to tumor progression. However, the ability of CAFs to regulate anoikis, detachment-induced cell death, has yet to be investigated. Here, a new role for CAFs in blocking anoikis in multiple cell lines, facilitating luminal filling in three-dimensional cell culture, and promoting anchorage-independent growth is defined. In addition, a novel mechanism underlying anoikis inhibition is discovered. Importantly, it was demonstrated that CAFs secrete elevated quantities of insulin-like growth factor-binding proteins (IGFBPs) that are both necessary for CAF-mediated anoikis inhibition and sufficient to block anoikis in the absence of CAFs. Furthermore, these data reveal a unique antiapoptotic mechanism for IGFBPs: the stabilization of the antiapoptotic protein Mcl-1. In aggregate, these data delineate a novel role for CAFs in promoting cell survival during detachment and unveil an additional mechanism by which the tumor microenvironment contributes to cancer progression. These results also identify IGFBPs as potential targets for the development of novel chemotherapeutics designed to eliminate detached cancer cells.
  
  
  CONCLUSIONS
  The ability of CAF-secreted IGFBPs to block anoikis in breast cancer represents a novel target for the development of therapeutics aimed at specifically eliminating extracellular matrix-detached breast cancer cells.
authors.affiliation: Authors' Affiliations: Departments of Biological Sciences and.
authors.forename: Kelsey J
authors.initials: KJ
authors.lastname: Weigel
authors.affiliation: Authors' Affiliations: Departments of Biological Sciences and.
authors.forename: Ana
authors.initials: A
authors.lastname: Jakimenko
authors.affiliation: Authors' Affiliations: Departments of Biological Sciences and.
authors.forename: Brooke A
authors.initials: BA
authors.lastname: Conti
authors.affiliation: Notre Dame Integrated Imaging Facility, University of Notre Dame, Notre Dame; and.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Chapman
authors.affiliation: South Bend Medical Foundation, South Bend, Indiana.
authors.forename: William J
authors.initials: WJ
authors.lastname: Kaliney
authors.affiliation: Authors' Affiliations: Departments of Biological Sciences and Notre Dame Integrated Imaging Facility, University of Notre Dame, Notre Dame; and.
authors.forename: W Matthew
authors.initials: WM
authors.lastname: Leevy
authors.affiliation: Chemistry and Biochemistry.
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Champion
authors.affiliation: Authors' Affiliations: Departments of Biological Sciences and zschafe1@nd.edu.
authors.forename: Zachary T
authors.initials: ZT
authors.lastname: Schafer
mesh_terms: D000818:Animals; D023102:Anoikis / Q000502:physiology*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D064593:Heterografts; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude
chemical_list: D018969:Insulin-Like Growth Factor Binding Proteins