Differential regulation of ErbB2 expression by cAMP-dependent protein kinase in tamoxifen-resistant breast cancer cells.
Acquired resistance to tamoxifen (TAM) is a serious therapeutic problem in breast cancer patients, and Her-2/ErbB2 expression is associated with decreased sensitivity to TAM. We previously reported that cAMP-dependent protein kinase (PKA)-mediated activator protein-2 (AP-2) activation was responsible for the expression of Her-2/ErbB2 in p53-inactivated mammary epithelial cells (Yang et al., 2006). In the present study, we tested the hypothesis that PKA plays a role in the expression of ErbB2 in tamoxifen-resistant breast cancer cells. Treatment with H-89, a specific PKA inhibitor, suppressed 4-hydroxytamoxifen-induced ErbB2 expression in control MCF-7 cells. In contrast, PKA inhibition by H-89 or cAMP-dependent protein kinase inhibitor l gamma overexpression increased the expression levels of ErbB2 in TAM-resistant MCF-7 (TAMR-MCF-7) cells. Transcriptional regulation of the erbB2 gene depends on two transcription factors, AP-2 and polyomavirus enhancer activator3 (PEA3). H-89 decreased nuclear or total levels of PEA3 in TAMR-MCF-7 cells. Chromatin immunoprecipitation assay results revealed that H-89 treatment reduced PEA3 binding to the proximal Ets binding site of the erbB2 gene promoter. Reporter gene analyses using human erbB2 gene promoter supported the critical role of PEA3 in the overexpression of ErbB2 in TAMR-MCF-7 cells treated with H-89. This deregulated PKA signaling cascades required for the ErbB2 expression may be important for the differential response of TAM-resistant breast cancer cells to EGF/ErbB2 stimuli.
Yang
Jin Won
JW
BK21 Project Team, College of Pharmacy, Chosun University, 375 Seosuk-dong, Dong-gu, Gwangju 501-759, Korea.
Kim
Mi Ra
MR
Kim
Hyung Gyoon
HG
Kim
Sang Kyum
SK
Jeong
Hye Gwang
HG
Kang
Keon Wook
KW
D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology* / Q000627:therapeutic use; D050656:Transcription Factor AP-2 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection
D018931:Antineoplastic Agents, Hormonal; D017868:Cyclic AMP-Dependent Protein Kinases; D047908:Intracellular Signaling Peptides and Proteins; D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; D013449:Sulfonamides; D013629:Tamoxifen; D050656:Transcription Factor AP-2; D014157:Transcription Factors; C107592:PKIG protein, human; C065788:transcription factor PEA3; C016601:afimoxifene; C508053:ERBB2 protein, human; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide