title: Hyperglycemia enhances the proliferation of non-tumorigenic and malignant mammary epithelial cells through increased leptin/IGF1R signaling and activation of AKT/mTOR.
abstract: Obesity and diabetes are associated with increased breast cancer risk and worse disease progression once cancer is diagnosed; however, the exact etiology behind these observations remains to be fully elucidated. Due to the global obesity/diabetes pandemic, it is imperative to understand how these diseases promote and enhance breast cancer and other common cancers. In this study we demonstrate that hyperglycemia promotes breast cancer by altering leptin/IGF1R and AKT/mTOR signaling. To our knowledge, we show for the first time that in breast epithelial cells, hyperglycemia alone directly impacts leptin signaling. Hyperglycemia increased proliferation of both non-tumorigenic and malignant mammary epithelial cells. These observations coincided with increased leptin receptor and IGF1R receptor, as well as, increased levels of GRB2, pJAK2, pSTAT3, pIRS1/2, pAKT, and p-mTOR. Moreover, pJAK2 was almost completely colocalized with leptin receptor under high glucose conditions. These results demonstrate how hyperglycemia can potentially increase the risk of breast cancer in premalignant lesions and enhance cancer progression in malignant cells.
authors.affiliation: Center of Excellence in Cancer Research, Center of Excellence in Diabetes Research, Department of Biomedical Sciences MSB1, Texas Tech University Health Sciences Center, Paul L. Foster School of Medicine, El Paso, Texas, United States of America.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Lopez
authors.forename: Arunkumar
authors.initials: A
authors.lastname: Arumugam
authors.forename: Riya
authors.initials: R
authors.lastname: Joseph
authors.forename: Kanika
authors.initials: K
authors.lastname: Monga
authors.forename: Thiyagarajan
authors.initials: T
authors.lastname: Boopalan
authors.forename: Pamela
authors.initials: P
authors.lastname: Agullo
authors.forename: Christina
authors.initials: C
authors.lastname: Gutierrez
authors.forename: Sushmita
authors.initials: S
authors.lastname: Nandy
authors.forename: Ramadevi
authors.initials: R
authors.lastname: Subramani
authors.forename: Jose Manuel
authors.initials: JM
authors.lastname: de la Rosa
authors.forename: Rajkumar
authors.initials: R
authors.lastname: Lakshmanaswamy
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005455:Fluorescent Antibody Technique; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism* / Q000473:pathology*; D015151:Immunoblotting; D020738:Leptin / Q000378:metabolism*; D061986:MCF-7 Cells; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D020738:Leptin; C546842:MTOR protein, human; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D005947:Glucose