title: CD24 cell surface expression in Mvt1 mammary cancer cells serves as a biomarker for sensitivity to anti-IGF1R therapy.
abstract: The pro-tumorigenic effects of the insulin-like growth factor receptor (IGF1R) are well described. IGF1R promotes cancer cell survival and proliferation and prevents apoptosis, and, additionally it was shown that IGF1R levels are significantly elevated in most common human malignancies including breast cancer. However, results from phase 3 clinical trials in unselected patients demonstrated lack of efficacy for anti-IGF1R therapy. These findings suggest that predictive biomarkers are greatly warranted in order to identify patients that will benefit from anti-IGF1R therapeutic strategies.
  
  
  
  Using the delivery of shRNA vectors into the Mvt1 cell line, we tested the role of the IGF1R in the development of mammary tumors. Based on CD24 cell surface expression, control and IGF1R-knockdown (IGF1R-KD) cells were FACS sorted into CD24(-) and CD24(+) subsets and further characterized in vitro. The tumorigenic capacity of each was determined following orthotopic inoculation into the mammary fat pad of female mice. Tumor cells were FACS characterized upon sacrifice to determine IGF1R effect on the plasticity of this cell's phenotype. Metastatic capacity of the cells was assessed using the tail vein assay.
  
  
  
  In this study we demonstrate that downregulation of the IGF1R specifically in cancer cells expressing CD24 on the cell surface membrane affect both their morphology (from mesenchymal-like into epithelial-like morphology) and phenotype in vitro. Moreover, we demonstrate that IGF1R-KD abolished both CD24(+) cells capacity to form mammary tumors and lung metastatic lesions. We found in both cells and tumors a marked upregulation in CTFG and a significant reduction of SLP1 expression in the CD24(+)/IGF1R-KD; tumor-suppressor and tumor-promoting genes respectively. Moreover, we demonstrate here that the IGF1R is essential for the maintenance of stem/progenitor-like cancer cells and we further demonstrate that IGF1R-KD induces in vivo differentiation of the CD24(+) cells toward the CD24(-) phenotype. This further supports the antitumorigenic effects of IGF1R-KD, as we recently published that these differentiated cells demonstrate significantly lower tumorigenic capacity compared with their CD24(+) counterparts.
  
  
  
  Taken together these findings suggest that CD24 cell surface expression may serve as a valuable biomarker in order to identify mammary tumors that will positively respond to targeted IGF1R therapies.
authors.affiliation: Diabetes and Metabolism Clinical Research Center of Excellence, Clinical Research Institute at Rambam (CRIR), Rambam Medical Center, Haifa, Israel.
authors.forename: Ran
authors.initials: R
authors.lastname: Rostoker
authors.affiliation: Diabetes and Metabolism Clinical Research Center of Excellence, Clinical Research Institute at Rambam (CRIR), Rambam Medical Center, Haifa, Israel.
authors.forename: Sarit
authors.initials: S
authors.lastname: Ben-Shmuel
authors.affiliation: Diabetes and Metabolism Clinical Research Center of Excellence, Clinical Research Institute at Rambam (CRIR), Rambam Medical Center, Haifa, Israel.|The Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.
authors.forename: Rola
authors.initials: R
authors.lastname: Rashed
authors.affiliation: Diabetes and Metabolism Clinical Research Center of Excellence, Clinical Research Institute at Rambam (CRIR), Rambam Medical Center, Haifa, Israel.
authors.forename: Zila
authors.initials: Z
authors.lastname: Shen Orr
authors.affiliation: Diabetes and Metabolism Clinical Research Center of Excellence, Clinical Research Institute at Rambam (CRIR), Rambam Medical Center, Haifa, Israel. derek.leroith@mssm.edu.|Department of Medicine, Icahn School of Medicine at Mt Sinai, New York City, NY, USA. derek.leroith@mssm.edu.
authors.forename: Derek
authors.initials: D
authors.lastname: LeRoith
mesh_terms: D000818:Animals; D015415:Biomarkers; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D051927:CD24 Antigen / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D016130:Immunophenotyping; D015674:Mammary Neoplasms, Animal; D051379:Mice; D009362:Neoplasm Metastasis; D034622:RNA Interference; D017526:Receptor, IGF Type 1 / Q000235:genetics* / Q000378:metabolism; D053481:Secretory Leukocyte Peptidase Inhibitor / Q000235:genetics / Q000378:metabolism
chemical_list: D015415:Biomarkers; D051927:CD24 Antigen; D053481:Secretory Leukocyte Peptidase Inhibitor; D055513:Connective Tissue Growth Factor; D017526:Receptor, IGF Type 1
keywords: CD24; IGF1R; Mammary tumor