title: Osteopontin increases breast cancer cell sensitivity to specific signaling pathway inhibitors in preclinical models.
abstract: Src kinase and Hsp90 play important roles in malignancy-promoting signaling pathways in a variety of cancers and related targeting agents are presently in clinical trials. To help improve the success of Src kinase and Hsp90 inhibitor therapies, identifying sensitive patient populations will be essential. Osteopontin (OPN), a secreted integrin-binding glycophosphoprotein, is associated with progression and metastasis in a variety of cancers and has been studied as a prognostic marker. Previous work of ours and other groups has indicated that OPN-induced signal transduction involves activation of both Src and Hsp90-dependent pathways. We thus hypothesized that over-expression of OPN could make tumor cells more vulnerable to these classes of inhibitors. This study used multiple in vitro assays to determine if OPN levels could predict breast cancer cell sensitivity to Hsp90 and/or Src kinase inhibitors. We used multiple derivatives of two unrelated of human breast cancer cell lines, high vs. low levels of OPN, to determine if OPN affects the response to two specific inhibitors, an Hsp90 inhibitor and a Src kinase inhibitor, in in vitro migration and colony formation assays. Cells had greater decreases in migration and colony forming ability after Hsp90 and Src kinase inhibitor treatments when OPN was present (either endogenous or exogenous). Decreasing OPN levels via shRNA knockdown decreased inhibitor effects. In rescue experiments, adding exogenous OPN to non-expressing cells increased inhibitor effects. These results suggest that OPN could potentially be useful clinically as a predictive marker in identifying patients who will benefit from either Hsp90 or Src kinase inhibitor therapy.
authors.affiliation: London Regional Cancer Program, London Health Sciences Centre, London, Ontario, Canada.
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Mutrie
authors.forename: Ann F
authors.initials: AF
authors.lastname: Chambers
authors.forename: Alan B
authors.initials: AB
authors.lastname: Tuck
mesh_terms: D052117:Benzodioxoles / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D005260:Female; D055785:Gene Knockdown Techniques; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D008954:Models, Biological; D014411:Neoplastic Stem Cells / Q000187:drug effects; D053495:Osteopontin / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D015398:Signal Transduction; D014162:Transfection; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
chemical_list: D052117:Benzodioxoles; D018841:HSP90 Heat-Shock Proteins; D011799:Quinazolines; D034741:RNA, Small Interfering; D053495:Osteopontin; C515233:saracatinib; D019061:src-Family Kinases