Selective induction of chemotherapy resistance of mammary tumors in a conditional mouse model for hereditary breast cancer.
We have studied in vivo responses of "spontaneous" Brca1- and p53-deficient mammary tumors arising in conditional mouse mutants to treatment with doxorubicin, docetaxel, or cisplatin. Like human tumors, the response of individual mouse tumors varies, but eventually they all become resistant to the maximum tolerable dose of doxorubicin or docetaxel. The tumors also respond well to cisplatin but do not become resistant, even after multiple treatments in which tumors appear to regrow from a small fraction of surviving cells. Classical biochemical resistance mechanisms, such as up-regulated drug transporters, appear to be responsible for doxorubicin resistance, rather than alterations in drug-damage effector pathways. Our results underline the promise of these mouse tumors for the study of tumor-initiating cells and of drug therapy of human cancer.
Rottenberg
Sven
S
Division of Molecular Biology and Center of Biomedical Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
Nygren
Anders O H
AO
Pajic
Marina
M
van Leeuwen
Fijs W B
FW
van der Heijden
Ingrid
I
van de Wetering
Koen
K
Liu
Xiaoling
X
de Visser
Karin E
KE
Gilhuijs
Kenneth G
KG
van Tellingen
Olaf
O
Schouten
Jan P
JP
Jonkers
Jos
J
Borst
Piet
P
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D019313:BRCA1 Protein / Q000172:deficiency; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use; D000077143:Docetaxel; D004317:Doxorubicin / Q000494:pharmacology / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D051379:Mice; D009368:Neoplasm Transplantation; D043823:Taxoids / Q000494:pharmacology / Q000627:therapeutic use; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency; D000097202:ATP-Binding Cassette Sub-Family B Member 4
D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D019313:BRCA1 Protein; D002945:Cisplatin; D000077143:Docetaxel; D004317:Doxorubicin; D043823:Taxoids; D016159:Tumor Suppressor Protein p53; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C095122:multidrug resistance protein 3