title: Integration of Downstream Signals of Insulin-like Growth Factor-1 Receptor by Endoplasmic Reticulum Stress for Estrogen-Induced Growth or Apoptosis in Breast Cancer Cells.
abstract: Estrogen (E2) exerts a dual function on E2-deprived breast cancer cells, with both initial proliferation and subsequent induction of stress responses to cause apoptosis. However, the mechanism by which E2 integrally regulates cell growth or apoptosis-associated pathways remains to be elucidated. Here, E2 deprivation results in many alterations in stress-responsive pathways. For instance, E2-deprived breast cancer cells had higher basal levels of stress-activated protein kinase, c-Jun N-terminal kinase (JNK), compared with wild-type MCF-7 cells. E2 treatment further constitutively activated JNK after 24 hours. However, inhibition of JNK (SP600125) was unable to abolish E2- induced apoptosis, whereas SP600125 alone arrested cells at the G2 phase of the cell cycle and increased apoptosis. Further examination showed that inhibition of JNK increased gene expression of TNFα and did not effectively attenuate expression of apoptosis-related genes induced by E2. A notable finding was that E2 regulated both JNK and Akt as the downstream signals of insulin-like growth factor-1 receptor (IGFIR)/PI3K, but with distinctive modulation patterns: JNK was constitutively activated, whereas Akt and Akt-associated proteins, such as PTEN and mTOR, were selectively degraded. Endoplasmic reticulum-associated degradation (ERAD) was involved in the selective protein degradation. These findings highlight a novel IGFIR/PI3K/JNK axis that plays a proliferative role during the prelude to E2-induced apoptosis and that the endoplasmic reticulum is a key regulatory site to decide cell fate after E2 treatment.
  
  
  CONCLUSIONS
  This study provides a new rationale for further exploration of E2-induced apoptosis to improve clinical benefit.
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia. Department of Breast Medical Oncology, MD Anderson Cancer Center, Houston, Texas.
authors.forename: Ping
authors.initials: P
authors.lastname: Fan
authors.affiliation: Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
authors.forename: Heather E
authors.initials: HE
authors.lastname: Cunliffe
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia. Department of Breast Medical Oncology, MD Anderson Cancer Center, Houston, Texas.
authors.forename: Philipp Y
authors.initials: PY
authors.lastname: Maximov
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia.
authors.forename: Fadeke A
authors.initials: FA
authors.lastname: Agboke
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia.
authors.forename: Russell E
authors.initials: RE
authors.lastname: McDaniel
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Zou
authors.affiliation: Computational Biology Division, The Translational Genomics Research Institute, Phoenix, Arizona.
authors.forename: Pilar
authors.initials: P
authors.lastname: Ramos
authors.affiliation: Computational Biology Division, The Translational Genomics Research Institute, Phoenix, Arizona.
authors.forename: Megan L
authors.initials: ML
authors.lastname: Russell
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia. Department of Breast Medical Oncology, MD Anderson Cancer Center, Houston, Texas. VCJordan@mdanderson.org.
authors.forename: V Craig
authors.initials: VC
authors.lastname: Jordan
mesh_terms: D000873:Anthracenes / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001943:Breast Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology*; D004967:Estrogens / Q000172:deficiency / Q000494:pharmacology*; D005260:Female; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D020935:MAP Kinase Signaling System; D061986:MCF-7 Cells; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism*
chemical_list: D000873:Anthracenes; D004967:Estrogens; D047428:Protein Kinase Inhibitors; C432165:pyrazolanthrone; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; D048670:MAP Kinase Kinase 4