Document Detail


Estrogen-dependent, tamoxifen-resistant tumorigenic growth of MCF-7 cells transfected with HER2/neu.
MedLine Citation:
PMID:  8095168     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Since the poor prognosis associated with HER2 amplified breast cancers might be explained by a mechanistic association between p185HER2 overexpression and therapeutic resistance, we assessed the chemo-endocrine sensitivity of estrogen receptor (ER) containing MCF-7 breast cancer cells transfected with full-length HER2 cDNA. Of the 36 isolated MCF/HER2 subclones, 7 were found to overexpress p185HER2 surface receptor at levels 3 to 45-fold greater than parental or control transfected cells (MCF/neo). The overexpressing transfectants possessed increased inositol-1,4,5-triphosphate-3'-kinase activity comparable to enzyme activity in the endogenously HER2 amplified breast cancer cell lines SK-Br-3 and BT-474. The anti-p185HER2 monoclonal antibody and receptor-specific partial agonist, muMAb4D5 (4D5), known to inhibit growth of SK-Br-3 and BT-474 cells, produced no significant growth inhibitory effect on any of the transfectants including the 45-fold overexpressing MCF/HER2-18 cells which were studied in greater detail. MCF/HER2-18 cells contained at least partially functioning exogenous receptor since 4D5 (3 micrograms/ml) specifically stimulated phosphorylation of p185HER2 and its co-precipitating ptyr56 substrate within 5 min, and this was followed at 1 h by a transient induction of c-myc but not c-fos mRNA. ER content and the in vitro sensitivity of MCF/HER2-18 cells to 5-fluorouracil and adriamycin were identical to those of control transfectants and parental cells. However, these highly overexpressing transfectants had acquired low level (2 to 4-fold) resistance to cisplatin and were no longer sensitive to the antiestrogen tamoxifen (TAM). To compare the hormone-dependent tumorigenicity of the HER2 transfectants, MCF/HER2-18 and control cells (MCF, MCF/neo-3) were implanted into ovariectomized athymic nude mice. No tumors were produced in the absence of estradiol (E2) administration. In E2 supplemented mice, MCF/HER2-18 tumors grew most rapidly. When E2 treatment was stopped and daily TAM injections were initiated, MCF-7 and MCF/neo-3 tumor growth ceased immediately, while MCF/HER2-18 tumors continued to show an accelerated growth rate lasting weeks. This pattern of hormone-dependent, TAM-resistant growth exhibited by the MCF/HER2-18 tumors in nude mice supports the possibility that p185HER2 overexpression in human breast cancers may be linked to therapeutic resistance.
Authors:
C C Benz; G K Scott; J C Sarup; R M Johnson; D Tripathy; E Coronado; H M Shepard; C K Osborne
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Breast cancer research and treatment     Volume:  24     ISSN:  0167-6806     ISO Abbreviation:  Breast Cancer Res. Treat.     Publication Date:  1992  
Date Detail:
Created Date:  1993-04-06     Completed Date:  1993-04-06     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  8111104     Medline TA:  Breast Cancer Res Treat     Country:  NETHERLANDS    
Other Details:
Languages:  eng     Pagination:  85-95     Citation Subset:  IM    
Affiliation:
Cancer Research Institute, University of California, San Francisco 94143.
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MeSH Terms
Descriptor/Qualifier:
Adenocarcinoma / genetics,  metabolism*,  pathology
Animals
Antibodies, Monoclonal / pharmacology
Breast Neoplasms / genetics,  metabolism*,  pathology
Cell Division / drug effects
Drug Resistance
Estrogens / pharmacology*
Female
Gene Expression Regulation, Neoplastic*
Humans
Mice
Mice, Nude
Phosphotransferases / drug effects,  metabolism*
Phosphotransferases (Alcohol Group Acceptor)*
Proto-Oncogene Proteins / genetics,  metabolism*
Receptor, erbB-2
Tamoxifen / pharmacology*
Transfection
Tumor Cells, Cultured
Grant Support
ID/Acronym/Agency:
CA-30251/CA/NCI NIH HHS; CA-36773/CA/NCI NIH HHS; CA-44768/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antibodies, Monoclonal; 0/Estrogens; 0/Proto-Oncogene Proteins; 10540-29-1/Tamoxifen; EC 2.7.-/Phosphotransferases; EC 2.7.1.-/Phosphotransferases (Alcohol Group Acceptor); EC 2.7.1.127/Inositol 1,4,5-trisphosphate 3-kinase; EC 2.7.10.1/Receptor, erbB-2

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