title: Highly specific role of the insulin receptor in breast cancer progression.
abstract: Accumulating evidence from clinical trials indicates that specific targeting of the IGF1 receptor (IGF1R) is not efficient as an anti-breast cancer treatment. One possible reason is that the mitogenic signals from the insulin receptor (IR) can be processed independently or as compensation to inhibition of the IGF1R. In this study, we highlight the role of the IR in mediating breast tumor progression in both WT mice and a hyperinsulinemic MKR mouse model by induction of Ir (Insr) or Igf1r knockdown (KD) in the mammary carcinoma Mvt-1 cell line. By using the specific IR antagonist-S961, we demonstrated that Igf1r-KD induces elevated responses by the IR to IGF1. On the other hand, Ir-KD cells generated significantly smaller tumors in the mammary fat pads of both WT and MKR mice, as opposed to control cells, whereas the Igf1r-KD cells did not. The tumorigenic effects of insulin on the Mvt-1 cells were also demonstrated using microarray analysis, which indicates alteration of genes and signaling pathways involved in proliferation, the cell cycle, and apoptosis following insulin stimulation. In addition, the correlation between IR and the potential prognostic marker for aggressive breast cancer, CD24, was examined in the Ir-KD cells. Fluorescence-activated cell sorting (FACS) analysis revealed more than 60% reduction in CD24 expression in the Ir-KD cells when compared with the control cells. Our results also indicate that CD24-expressing cells can restore, at least in part, the tumorigenic capacity of Ir-KD cells. Taken together, our results highlight the mitogenic role of the IR in mammary tumor progression with a direct link to CD24 expression.
authors.affiliation: Clinical Research Institute at Rambam (CRIR) and the Faculty of MedicineTechnion, Diabetes and Metabolism Clinical Research Center of Excellence, Haifa, IsraelThe Laboratory of Molecular MedicineRambam Health Care Campus and Rappaport Faculty of Medicine and Research Institute, Technion, Haifa 31096, IsraelDivision of EndocrinologyDiabetes and Bone Diseases, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.
authors.forename: Ran
authors.initials: R
authors.lastname: Rostoker
authors.affiliation: Clinical Research Institute at Rambam (CRIR) and the Faculty of MedicineTechnion, Diabetes and Metabolism Clinical Research Center of Excellence, Haifa, IsraelThe Laboratory of Molecular MedicineRambam Health Care Campus and Rappaport Faculty of Medicine and Research Institute, Technion, Haifa 31096, IsraelDivision of EndocrinologyDiabetes and Bone Diseases, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.
authors.forename: Sagi
authors.initials: S
authors.lastname: Abelson
authors.affiliation: Clinical Research Institute at Rambam (CRIR) and the Faculty of MedicineTechnion, Diabetes and Metabolism Clinical Research Center of Excellence, Haifa, IsraelThe Laboratory of Molecular MedicineRambam Health Care Campus and Rappaport Faculty of Medicine and Research Institute, Technion, Haifa 31096, IsraelDivision of EndocrinologyDiabetes and Bone Diseases, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.
authors.forename: Keren
authors.initials: K
authors.lastname: Bitton-Worms
authors.affiliation: Clinical Research Institute at Rambam (CRIR) and the Faculty of MedicineTechnion, Diabetes and Metabolism Clinical Research Center of Excellence, Haifa, IsraelThe Laboratory of Molecular MedicineRambam Health Care Campus and Rappaport Faculty of Medicine and Research Institute, Technion, Haifa 31096, IsraelDivision of EndocrinologyDiabetes and Bone Diseases, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.
authors.forename: Inna
authors.initials: I
authors.lastname: Genkin
authors.affiliation: Clinical Research Institute at Rambam (CRIR) and the Faculty of MedicineTechnion, Diabetes and Metabolism Clinical Research Center of Excellence, Haifa, IsraelThe Laboratory of Molecular MedicineRambam Health Care Campus and Rappaport Faculty of Medicine and Research Institute, Technion, Haifa 31096, IsraelDivision of EndocrinologyDiabetes and Bone Diseases, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.
authors.forename: Sarit
authors.initials: S
authors.lastname: Ben-Shmuel
authors.affiliation: Clinical Research Institute at Rambam (CRIR) and the Faculty of MedicineTechnion, Diabetes and Metabolism Clinical Research Center of Excellence, Haifa, IsraelThe Laboratory of Molecular MedicineRambam Health Care Campus and Rappaport Faculty of Medicine and Research Institute, Technion, Haifa 31096, IsraelDivision of EndocrinologyDiabetes and Bone Diseases, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Dakwar
authors.affiliation: Clinical Research Institute at Rambam (CRIR) and the Faculty of MedicineTechnion, Diabetes and Metabolism Clinical Research Center of Excellence, Haifa, IsraelThe Laboratory of Molecular MedicineRambam Health Care Campus and Rappaport Faculty of Medicine and Research Institute, Technion, Haifa 31096, IsraelDivision of EndocrinologyDiabetes and Bone Diseases, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.
authors.forename: Zila Shen
authors.initials: ZS
authors.lastname: Orr
authors.affiliation: Clinical Research Institute at Rambam (CRIR) and the Faculty of MedicineTechnion, Diabetes and Metabolism Clinical Research Center of Excellence, Haifa, IsraelThe Laboratory of Molecular MedicineRambam Health Care Campus and Rappaport Faculty of Medicine and Research Institute, Technion, Haifa 31096, IsraelDivision of EndocrinologyDiabetes and Bone Diseases, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.
authors.forename: Avishay
authors.initials: A
authors.lastname: Caspi
authors.affiliation: Clinical Research Institute at Rambam (CRIR) and the Faculty of MedicineTechnion, Diabetes and Metabolism Clinical Research Center of Excellence, Haifa, IsraelThe Laboratory of Molecular MedicineRambam Health Care Campus and Rappaport Faculty of Medicine and Research Institute, Technion, Haifa 31096, IsraelDivision of EndocrinologyDiabetes and Bone Diseases, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.
authors.forename: Maty
authors.initials: M
authors.lastname: Tzukerman
authors.affiliation: Clinical Research Institute at Rambam (CRIR) and the Faculty of MedicineTechnion, Diabetes and Metabolism Clinical Research Center of Excellence, Haifa, IsraelThe Laboratory of Molecular MedicineRambam Health Care Campus and Rappaport Faculty of Medicine and Research Institute, Technion, Haifa 31096, IsraelDivision of EndocrinologyDiabetes and Bone Diseases, Icahn School of Medicine at Mount Sinai, New York City, New York, USA Clinical Research Institute at Rambam (CRIR) and the Faculty of MedicineTechnion, Diabetes and Metabolism Clinical Research Center of Excellence, Haifa, IsraelThe Laboratory of Molecular MedicineRambam Health Care Campus and Rappaport Faculty of Medicine and Research Institute, Technion, Haifa 31096, IsraelDivision of EndocrinologyDiabetes and Bone Diseases, Icahn School of Medicine at Mount Sinai, New York City, New York, USA d_leroith@rambam.health.gov.il.
authors.forename: Derek
authors.initials: D
authors.lastname: LeRoith
mesh_terms: D000818:Animals; D051927:CD24 Antigen / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D007328:Insulin / Q000494:pharmacology; D015674:Mammary Neoplasms, Animal / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism*; D015398:Signal Transduction; D047368:Tumor Burden
chemical_list: D051927:CD24 Antigen; C497890:Cd24a protein, mouse; D007328:Insulin; D019869:Phosphatidylinositol 3-Kinases; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases
keywords: breast cancer and CD24; hyperinsulinemia; insulin receptor; insulin-like growth factor 1 receptor