Insulin-like growth factor-1 receptor signaling increases the invasive potential of human epidermal growth factor receptor 2-overexpressing breast cancer cells via Src-focal adhesion kinase and forkhead box protein M1.
Resistance to the human epidermal growth factor receptor (HER2)-targeted antibody trastuzumab is a major clinical concern in the treatment of HER2-positive metastatic breast cancer. Increased expression or signaling from the insulin-like growth factor-1 receptor (IGF-1R) has been reported to be associated with trastuzumab resistance. However, the specific molecular and biologic mechanisms through which IGF-1R promotes resistance or disease progression remain poorly defined. In this study, we found that the major biologic effect promoted by IGF-1R was invasion, which was mediated by both Src-focal adhesion kinase (FAK) signaling and Forkhead box protein M1 (FoxM1). Cotargeting IGF-1R and HER2 using either IGF-1R antibodies or IGF-1R short hairpin RNA in combination with trastuzumab resulted in significant but modest growth inhibition. Reduced invasion was the most significant biologic effect achieved by cotargeting IGF-1R and HER2 in trastuzumab-resistant cells. Constitutively active Src blocked the anti-invasive effect of IGF-1R/HER2 cotargeted therapy. Furthermore, knockdown of FoxM1 blocked IGF-1-mediated invasion, and dual targeting of IGF-1R and HER2 reduced expression of FoxM1. Re-expression of FoxM1 restored the invasive potential of IGF-1R knockdown cells treated with trastuzumab. Overall, our results strongly indicate that therapeutic combinations that cotarget IGF-1R and HER2 may reduce the invasive potential of cancer cells that are resistant to trastuzumab through mechanisms that depend in part on Src and FoxM1.
Departments of Pharmacology (E.S.-F., S.M.D., R.N.) and Hematology and Medical Oncology (E.P., L.T.-S., R.N.), School of Medicine, and Molecular and Systems Pharmacology Program, Graduate Division of Biological and Biomedical Sciences (E.S.-F., R.N.), and Winship Cancer Institute (R.C.C., E.P., L.T.-S., R.N.), Emory University, Atlanta, Georgia; Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, Georgia (M.C.B., R.C.C.); and Departments of Obstetrics and Gynecology and Microbiology, James Cancer Hospital, Solove Research Institute and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio (K.C.F., P.T.P.K.).
Eduardo
E
Sanabria-Figueroa
Departments of Pharmacology (E.S.-F., S.M.D., R.N.) and Hematology and Medical Oncology (E.P., L.T.-S., R.N.), School of Medicine, and Molecular and Systems Pharmacology Program, Graduate Division of Biological and Biomedical Sciences (E.S.-F., R.N.), and Winship Cancer Institute (R.C.C., E.P., L.T.-S., R.N.), Emory University, Atlanta, Georgia; Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, Georgia (M.C.B., R.C.C.); and Departments of Obstetrics and Gynecology and Microbiology, James Cancer Hospital, Solove Research Institute and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio (K.C.F., P.T.P.K.).
Siobhan M
SM
Donnelly
Departments of Pharmacology (E.S.-F., S.M.D., R.N.) and Hematology and Medical Oncology (E.P., L.T.-S., R.N.), School of Medicine, and Molecular and Systems Pharmacology Program, Graduate Division of Biological and Biomedical Sciences (E.S.-F., R.N.), and Winship Cancer Institute (R.C.C., E.P., L.T.-S., R.N.), Emory University, Atlanta, Georgia; Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, Georgia (M.C.B., R.C.C.); and Departments of Obstetrics and Gynecology and Microbiology, James Cancer Hospital, Solove Research Institute and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio (K.C.F., P.T.P.K.).
Kevin C
KC
Foy
Departments of Pharmacology (E.S.-F., S.M.D., R.N.) and Hematology and Medical Oncology (E.P., L.T.-S., R.N.), School of Medicine, and Molecular and Systems Pharmacology Program, Graduate Division of Biological and Biomedical Sciences (E.S.-F., R.N.), and Winship Cancer Institute (R.C.C., E.P., L.T.-S., R.N.), Emory University, Atlanta, Georgia; Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, Georgia (M.C.B., R.C.C.); and Departments of Obstetrics and Gynecology and Microbiology, James Cancer Hospital, Solove Research Institute and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio (K.C.F., P.T.P.K.).
Meghan C
MC
Buss
Departments of Pharmacology (E.S.-F., S.M.D., R.N.) and Hematology and Medical Oncology (E.P., L.T.-S., R.N.), School of Medicine, and Molecular and Systems Pharmacology Program, Graduate Division of Biological and Biomedical Sciences (E.S.-F., R.N.), and Winship Cancer Institute (R.C.C., E.P., L.T.-S., R.N.), Emory University, Atlanta, Georgia; Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, Georgia (M.C.B., R.C.C.); and Departments of Obstetrics and Gynecology and Microbiology, James Cancer Hospital, Solove Research Institute and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio (K.C.F., P.T.P.K.).
Robert C
RC
Castellino
Departments of Pharmacology (E.S.-F., S.M.D., R.N.) and Hematology and Medical Oncology (E.P., L.T.-S., R.N.), School of Medicine, and Molecular and Systems Pharmacology Program, Graduate Division of Biological and Biomedical Sciences (E.S.-F., R.N.), and Winship Cancer Institute (R.C.C., E.P., L.T.-S., R.N.), Emory University, Atlanta, Georgia; Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, Georgia (M.C.B., R.C.C.); and Departments of Obstetrics and Gynecology and Microbiology, James Cancer Hospital, Solove Research Institute and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio (K.C.F., P.T.P.K.).
Elisavet
E
Paplomata
Departments of Pharmacology (E.S.-F., S.M.D., R.N.) and Hematology and Medical Oncology (E.P., L.T.-S., R.N.), School of Medicine, and Molecular and Systems Pharmacology Program, Graduate Division of Biological and Biomedical Sciences (E.S.-F., R.N.), and Winship Cancer Institute (R.C.C., E.P., L.T.-S., R.N.), Emory University, Atlanta, Georgia; Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, Georgia (M.C.B., R.C.C.); and Departments of Obstetrics and Gynecology and Microbiology, James Cancer Hospital, Solove Research Institute and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio (K.C.F., P.T.P.K.).
Latonia
L
Taliaferro-Smith
Departments of Pharmacology (E.S.-F., S.M.D., R.N.) and Hematology and Medical Oncology (E.P., L.T.-S., R.N.), School of Medicine, and Molecular and Systems Pharmacology Program, Graduate Division of Biological and Biomedical Sciences (E.S.-F., R.N.), and Winship Cancer Institute (R.C.C., E.P., L.T.-S., R.N.), Emory University, Atlanta, Georgia; Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, Georgia (M.C.B., R.C.C.); and Departments of Obstetrics and Gynecology and Microbiology, James Cancer Hospital, Solove Research Institute and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio (K.C.F., P.T.P.K.).
Pravin T P
PT
Kaumaya
Departments of Pharmacology (E.S.-F., S.M.D., R.N.) and Hematology and Medical Oncology (E.P., L.T.-S., R.N.), School of Medicine, and Molecular and Systems Pharmacology Program, Graduate Division of Biological and Biomedical Sciences (E.S.-F., R.N.), and Winship Cancer Institute (R.C.C., E.P., L.T.-S., R.N.), Emory University, Atlanta, Georgia; Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, Georgia (M.C.B., R.C.C.); and Departments of Obstetrics and Gynecology and Microbiology, James Cancer Hospital, Solove Research Institute and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio (K.C.F., P.T.P.K.) rnahta@emory.edu.
Rita
R
Nahta
D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000096:biosynthesis*; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000096:biosynthesis*; D015972:Gene Expression Regulation, Neoplastic; D016391:Genes, src / Q000502:physiology; D006801:Humans; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology
D051417:Focal Adhesion Kinase 1; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D017526:Receptor, IGF Type 1; C107585:FOXM1 protein, human; C508053:ERBB2 protein, human; C496050:PTK2 protein, human