PMID- 16584539
OWN - NLM
STAT- MEDLINE
DCOM- 20060731
LR  - 20220316
IS  - 1465-542X (Electronic)
IS  - 1465-5411 (Print)
IS  - 1465-5411 (Linking)
VI  - 8
IP  - 2
DP  - 2006
TI  - Type I insulin-like growth factor receptor over-expression induces proliferation 
      and anti-apoptotic signaling in a three-dimensional culture model of breast 
      epithelial cells.
PG  - R18
AB  - INTRODUCTION: Activation of the type I insulin-like growth factor receptor 
      (IGFIR) promotes proliferation and inhibits apoptosis in a variety of cell types. 
      Transgenic mice expressing a constitutively active IGFIR or IGF-I develop mammary 
      tumors and increased levels of IGFIR have been detected in primary breast 
      cancers. However, the contribution of IGFIR activation in promoting breast cancer 
      progression remains unknown. Mammary epithelial cell lines grown in 
      three-dimensional cultures form acinar structures that mimic the round, 
      polarized, hollow and growth-arrested features of mammary alveoli. We used this 
      system to determine how proliferation and survival signaling by IGFIR activation 
      affects breast epithelial cell biology and contributes to breast cancer 
      progression. METHODS: Pooled, stable MCF-10A breast epithelial cells expressing 
      wild-type IGFIR or kinase-dead IGFIR (K1003A) were generated using 
      retroviral-mediated gene transfer. The effects of over-expression of wild-type or 
      kinase-dead IGFIR on breast epithelial cell biology were analyzed by confocal 
      microscopy of three-dimensional cultures. The contribution of signaling pathways 
      downstream of IGFIR activation to proliferation and apoptosis were determined by 
      pharmacological inhibition of phosphatidylinositol 3' kinase (PI3K) with 
      LY294002, MAP kinase kinase (MEK) with UO126 and mammalian target of rapamycin 
      (mTOR) with rapamycin. RESULTS: We found that MCF-10A cells over-expressing the 
      IGFIR formed large, misshapen acinar structures with filled lumina and disrupted 
      apico-basal polarization. This phenotype was ligand-dependent, occurring with 
      IGF-I or supraphysiological doses of insulin, and did not occur in cells 
      over-expressing the kinase-dead receptor. We observed increased proliferation, 
      decreased apoptosis and increased phosphorylation of Ser473 of Akt and Ser2448 of 
      mTOR throughout IGFIR structures. Inhibition of PI3K with LY294002 or MEK with 
      UO126 prevented the development of acinar structures from IGFIR-expressing but 
      not control cells. The mTOR inhibitor rapamycin failed to prevent IGFIR-induced 
      hyperproliferation and survival signaling. CONCLUSION: Increased proliferation 
      and survival signaling as well as loss of apico-basal polarity by IGFIR 
      activation in mammary epithelial cells may promote early lesions of breast 
      cancer. Three-dimensional cultures of MCF-10A cells over-expressing the IGFIR are 
      a useful model with which to study the role of IGFIR signaling in breast cancer 
      progression and for characterizing the effects of chemotherapeutics targeted to 
      IGFIR signaling.
FAU - Yanochko, Gina M
AU  - Yanochko GM
AD  - Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, 
      La Jolla, CA 92037, USA. yanochko@salk.edu
FAU - Eckhart, Walter
AU  - Eckhart W
LA  - eng
GR  - CA14195/CA/NCI NIH HHS/United States
GR  - F32 CA099418-02/CA/NCI NIH HHS/United States
GR  - R01 CA013884/CA/NCI NIH HHS/United States
GR  - CA13884/CA/NCI NIH HHS/United States
GR  - F32 CA099418/CA/NCI NIH HHS/United States
GR  - P30 CA014195/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20060403
PL  - England
TA  - Breast Cancer Res
JT  - Breast cancer research : BCR
JID - 100927353
RN  - 0 (Insulin)
RN  - 62229-50-9 (Epidermal Growth Factor)
RN  - EC 2.7.10.1 (Receptor, IGF Type 1)
SB  - IM
MH  - Apoptosis/*physiology
MH  - Breast Neoplasms/*pathology/physiopathology
MH  - Cell Division/drug effects
MH  - Cell Line, Tumor
MH  - Cell Polarity
MH  - Cell Survival
MH  - Cells, Cultured
MH  - Epidermal Growth Factor/pharmacology
MH  - Epithelial Cells/*cytology/drug effects/*physiology
MH  - Gene Transfer Techniques
MH  - Humans
MH  - Insulin/pharmacology
MH  - Morphogenesis
MH  - Receptor, IGF Type 1/*genetics
MH  - Retroviridae
MH  - Signal Transduction/drug effects/*physiology
PMC - PMC1557721
EDAT- 2006/04/06 09:00
MHDA- 2006/08/01 09:00
PMCR- 2006/04/03
CRDT- 2006/04/06 09:00
PHST- 2005/12/07 00:00 [received]
PHST- 2006/02/14 00:00 [revised]
PHST- 2006/03/03 00:00 [accepted]
PHST- 2006/04/06 09:00 [pubmed]
PHST- 2006/08/01 09:00 [medline]
PHST- 2006/04/06 09:00 [entrez]
PHST- 2006/04/03 00:00 [pmc-release]
AID - bcr1392 [pii]
AID - 10.1186/bcr1392 [doi]
PST - ppublish
SO  - Breast Cancer Res. 2006;8(2):R18. doi: 10.1186/bcr1392. Epub 2006 Apr 3.