title: Silencing vimentin expression decreases pulmonary metastases in a pre-diabetic mouse model of mammary tumor progression.
abstract: Increased breast cancer risk and mortality has been associated with obesity and type 2 diabetes (T2D). Hyperinsulinemia, a key factor in obesity, pre-diabetes and T2D, has been associated with decreased breast cancer survival. In this study, a mouse model of pre-diabetes (MKR mouse) was used to investigate the mechanisms through which endogenous hyperinsulinemia promotes mammary tumor metastases. The MKR mice developed larger primary tumors and greater number of pulmonary metastases compared with wild-type (WT) mice after injection with c-Myc/Vegf overexpressing MVT-1 cells. Analysis of the primary tumors showed significant increase in vimentin protein expression in the MKR mice compared with WT. We hypothesized that vimentin was an important mediator in the effect of hyperinsulinemia on breast cancer metastasis. Lentiviral short hairpin RNA knockdown of vimentin led to a significant decrease in invasion of the MVT-1 cells and abrogated the increase in cell invasion in response to insulin. In the pre-diabetic MKR mouse, vimentin knockdown led to a decrease in pulmonary metastases. In vitro, we found that insulin increased pAKT, prevented caspase 3 activation, and increased vimentin. Inhibiting the phosphatidylinositol 3 kinase/AKT pathway, using NVP-BKM120, increased active caspase 3 and decreased vimentin levels. This study is the first to show that vimentin has an important role in tumor metastasis in vivo in the setting of pre-diabetes and endogenous hyperinsulinemia. Vimentin targeting may be an important therapeutic strategy to reduce metastases in patients with obesity, pre-diabetes or T2D.
authors: Division of Endocrinology, Diabetes and Bone Diseases, Icahn School of Medicine at Mount Sinai, New York City, NY, USA.
authors: Z
authors: Z
authors: Zelenko
authors: Division of Endocrinology, Diabetes and Bone Diseases, Icahn School of Medicine at Mount Sinai, New York City, NY, USA.
authors: E J
authors: EJ
authors: Gallagher
authors: Division of Endocrinology, Diabetes and Bone Diseases, Icahn School of Medicine at Mount Sinai, New York City, NY, USA.
authors: A
authors: A
authors: Tobin-Hess
authors: Division of Endocrinology, Diabetes and Bone Diseases, Icahn School of Medicine at Mount Sinai, New York City, NY, USA.
authors: V
authors: V
authors: Belardi
authors: Clinical Research Institute at Rambam (CRIR) and the Faculty of Medicine, Technion, Diabetes and Metabolism Clinical Research Center of Excellence, Haifa, Israel.
authors: R
authors: R
authors: Rostoker
authors: Division of Endocrinology, Diabetes and Bone Diseases, Icahn School of Medicine at Mount Sinai, New York City, NY, USA.
authors: J
authors: J
authors: Blank
authors: Division of Endocrinology, Diabetes and Bone Diseases, Icahn School of Medicine at Mount Sinai, New York City, NY, USA.
authors: Y
authors: Y
authors: Dina
authors: Division of Endocrinology, Diabetes and Bone Diseases, Icahn School of Medicine at Mount Sinai, New York City, NY, USA.|Clinical Research Institute at Rambam (CRIR) and the Faculty of Medicine, Technion, Diabetes and Metabolism Clinical Research Center of Excellence, Haifa, Israel.
authors: D
authors: D
authors: LeRoith
mesh_terms: D000818:Animals; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D020868:Gene Silencing; D007328:Insulin / Q000494:pharmacology; D008175:Lung Neoplasms / Q000556:secondary*; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D014746:Vimentin / Q000235:genetics*
chemical_list: D007328:Insulin; D014746:Vimentin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases