Enhanced expression of aromatase in p53-inactivated mammary epithelial cells.
Both the functional loss of p53 and the overexpression of aromatase are important for the progression of breast cancer in postmenopausal women. Here, we found that aromatase expression was up-regulated in primary cultures of mammary epithelial cells (p53(Delta)(5,6) MEC) isolated from mice with a defect in exons 5 and 6 of the p53 gene. Aromatase basal activity and expression levels were significantly increased in p53(Delta)(5,6) MEC when compared with wild-type MEC. Reporter gene activity in p53(Delta)(5,6) MEC transfected with the aromatase promoter or the cAMP-responsive element (CRE) minimal promoter was higher than wild-type MEC. p53 inactivation increased both Ser133-phosphorylated CRE-binding protein (CREB) and the nuclear accumulation of CREB. Inhibition of extracellular signal-regulated kinase (ERK) or Src tyrosine kinase blocked aromatase gene transactivation and CREB activation in the p53(Delta)(5,6) MEC. These results support the hypothesis that a genetic defect in the function of p53 enhances the expression of aromatase via ERK or Src activation in MEC, which suggests that aromatase expression is closely related to the p53 status in MEC.
Choi
Hoo Kyun
HK
BK21 Project Team, College of Pharmacy, Chosun University, Gwangju, South Korea.
Roh
Sang Hee
SH
Kim
Hyung Gyoun
HG
Han
Eun Hee
EH
Jeong
Hye Gwang
HG
Kang
Keon Wook
KW
D000818:Animals; D001141:Aromatase / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D004847:Epithelial Cells / Q000201:enzymology / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation; D019426:Integrases / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D019061:src-Family Kinases / Q000378:metabolism
C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D016159:Tumor Suppressor Protein p53; D000242:Cyclic AMP; D001141:Aromatase; D019061:src-Family Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; C045073:Cre recombinase; D019426:Integrases