Effects of c-erbB2 overexpression on the drug sensitivities of normal human mammary epithelial cells.
BACKGROUND
Overexpression of the gene c-erbB2, which encodes a receptor tyrosine kinase, in breast tumors has been linked with either increased or decreased response of breast cancer patients to various therapies. In breast cancer cell lines, overexpression of exogenous c-erbB2 sometimes alters drug sensitivities but sometimes has no effect. To avoid the genetic complexities associated with established cancer cell lines, normal human mammary epithelial cells (HMECs) were studied to determine whether c-erbB2 overexpression by itself would alter chemosensitivity.


METHODS
HMECs were designed to overexpress c-erbB2, and these cells were then evaluated for alterations in chemosensitivity.


RESULTS
HMECs overexpressing c-erbB2 failed to show any alterations in chemosensitivity to a panel of chemotherapeutic agents, as indicated by 95% confidence intervals on growth curves of cells treated with or without the agent of interest. With the use of fluorescence-activated cell sorting to enrich for HMECs overexpressing c-erbB2 on their surface, an 85% pure population of cells was isolated and their chemosensitivity was evaluated. Again, the cells failed to display any alterations in chemosensitivity.


CONCLUSIONS
These results suggest that overexpression of c-erbB2 is not sufficient by itself to induce changes in chemosensitivity. Cellular studies using normal human cells in which the complexity of the system can be carefully controlled by the addition of one, two, or even more genes associated with cancer development may provide valuable information about how the products of the genes interact with each other and which combinations are critical in regulating chemosensitivity.
Orr
M S
MS
Gene Logic Inc., Gaithersburg, MD 20878, USA. morr@genelogic.com
O'Connor
P M
PM
Kohn
K W
KW
D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D001940:Breast / Q000166:cytology / Q000187:drug effects*; D002478:Cells, Cultured; D002945:Cisplatin / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004847:Epithelial Cells / Q000187:drug effects*; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D005434:Flow Cytometry; D005472:Fluorouracil / Q000494:pharmacology; D018734:Genes, erbB-2; D006801:Humans; D008727:Methotrexate / Q000494:pharmacology; D017239:Paclitaxel / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D014161:Transduction, Genetic; D014162:Transfection; D015854:Up-Regulation
D000970:Antineoplastic Agents; D002945:Cisplatin; D004317:Doxorubicin; D005419:Flavonoids; D005472:Fluorouracil; D008727:Methotrexate; D017239:Paclitaxel; D010880:Piperidines; D018719:Erb-b2 Receptor Tyrosine Kinases; C077990:alvocidib