title: IGF-1 regulates Cyr61 induced breast cancer cell proliferation and invasion.
abstract: BACKGROUND
  Studies from our laboratory and others have shown that cysteine-rich 61 (Cyr61) may be involved in tumor proliferation and invasion. In earlier studies, we demonstrated increased insulin-like growth factor-I (IGF-1) is associated with breast tumor formation and poor clinical outcomes. In our current study we have investigated IGF-1 regulation of Cyr61 and whether targeting IGF-1 could inhibit Cyr61 induced tumor growth and proliferation.
  
  
  METHODS
  Several ATCC derived normal and breast cancer cell lines were used in this study: MDA-MB231, BT474, MCF-7, and SKBR3. We also tested cells stably transfected in our laboratory with active Akt1 (pAkt; SKBR3/AA and MCF-7/AA) and dominant negative Akt1 (SKBR3/DN and MCF-7/DN). In addition, we used MCF-7 cells transfected with full length Cyr61 (CYA). Monolayer cultures treated with IGF-1 were analyzed for Cyr61 expression by RT-PCR and immunohistochemical staining. Migration assays and MTT based proliferation assays were used to determine invasive characteristics in response to IGF-1/Cyr61 activation.
  
  
  RESULTS
  Cells with activated Akt have increased levels of Cyr61. Conversely, cells with inactive Akt have decreased levels of Cyr61. IGF-1 treatment increased Cyr61 expression significantly and cells with high level of Cyr61 demonstrate increased invasiveness and proliferation. Cyr61 overexpression and activation led to decrease in E-cadherin and decrease in FOXO1. Inhibition of the PI3K and MAPK pathways resulted in significant decrease in invasiveness and proliferation, most notably in the PI3K pathway inhibited cells.
  
  
  CONCLUSIONS
  The findings of this study show that IGF-1 upregulates Cyr61 primarily through activation of the Akt-PI3K pathway. IGF-1 induced MAPK plays a partial role. Increase in Cyr61 leads to increase in breast cancer cell growth and invasion. Hence, targeting Cyr61 and associated pathways may offer an opportunity to inhibit IGF-1 mediated Cyr61 induced breast cancer growth and invasion.
authors: Division of Cancer Research and Training, Center to Eliminate Cancer Health Disparities, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, California, United States of America.
authors: Suren
authors: S
authors: Sarkissyan
authors: Division of Cancer Research and Training, Center to Eliminate Cancer Health Disparities, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, California, United States of America.
authors: Marianna
authors: M
authors: Sarkissyan
authors: Division of Cancer Research and Training, Center to Eliminate Cancer Health Disparities, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, California, United States of America; Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, California, United States of America.
authors: Yanyuan
authors: Y
authors: Wu
authors: Division of Cancer Research and Training, Center to Eliminate Cancer Health Disparities, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, California, United States of America.
authors: Jessica
authors: J
authors: Cardenas
authors: Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, California, United States of America; Division of Hematology/Oncology, Department of Internal Medicine, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
authors: H Phillip
authors: HP
authors: Koeffler
authors: Division of Cancer Research and Training, Center to Eliminate Cancer Health Disparities, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, California, United States of America; Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, California, United States of America.
authors: Jaydutt V
authors: JV
authors: Vadgama
mesh_terms: D016475:3T3 Cells; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism*; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D055515:Cysteine-Rich Protein 61 / Q000235:genetics / Q000378:metabolism*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D020935:MAP Kinase Signaling System; D061986:MCF-7 Cells; D051379:Mice
chemical_list: D015820:Cadherins; D055515:Cysteine-Rich Protein 61; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D007334:Insulin-Like Growth Factor I