A new model of patient tumor-derived breast cancer xenografts for preclinical assays.
OBJECTIVE
To establish a panel of human breast cancer (HBC) xenografts in immunodeficient mice suitable for pharmacologic preclinical assays.


METHODS
200 samples of HBCs were grafted into Swiss nude mice. Twenty-five transplantable xenografts were established (12.5%). Their characterization included histology, p53 status, genetic analysis by array comparative genomic hybridization, gene expression by Western blotting, and quantitative reverse transcription-PCR. Biological profiles of nine xenografts were compared with those of the corresponding patient's tumor. Chemosensitivities of 17 xenografts to a combination of Adriamycin and cyclophosphamide (AC), docetaxel, trastuzumab, and Degarelix were evaluated.


RESULTS
Almost all patient tumors established as xenografts displayed an aggressive phenotype, i.e., high-grade, triple-negative status. The histology of the xenografts recapitulated the features of the original tumors. Mutation of p53 and inactivation of Rb and PTEN proteins were found in 83%, 30%, and 42% of HBC xenografts, respectively. Two HBCx had an ERBB2 (HER2) amplification. Large variations were observed in the expression of HER family receptors and in genomic profiles. Genomic alterations were close to those of original samples in paired tumors. Three xenografts formed lung metastases. A total of 15 of the 17 HBCx (88%) responded to AC, and 8 (47%) responded to docetaxel. One ERBB2-amplified xenograft responded to trastuzumab, whereas the other did not. The drug response of HBC xenografts was concordant with that of the patient's tumor in five of seven analyzable cases.


CONCLUSIONS
This panel of breast cancer xenografts includes 15 triple-negative, one ER positive and 2 ERBB2 positive. This panel represents a useful preclinical tool for testing new agents and protocols and for further exploration of the biological basis of drug responses.
Marangoni
Elisabetta
E
U612 Institut National de la Sante et de la Recherche Medicale, Pharmacologie Préclinique Antitumorale, Paris Anatomie et Cytologie Pathologique, Hôpital Trousseau, Tours, France.
Vincent-Salomon
Anne
A
Auger
Nathalie
N
Degeorges
Armelle
A
Assayag
Franck
F
de Cremoux
Patricia
P
de Plater
Ludmilla
L
Guyader
Charlotte
C
De Pinieux
Gonzague
G
Judde
Jean-Gabriel
JG
Rebucci
Magali
M
Tran-Perennou
Carine
C
Sastre-Garau
Xavier
X
Sigal-Zafrani
Brigitte
B
Delattre
Olivier
O
Diéras
Véronique
V
Poupon
Marie-France
MF
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D045744:Cell Line, Tumor; D003520:Cyclophosphamide / Q000008:administration & dosage; D004195:Disease Models, Animal; D000077143:Docetaxel; D004317:Doxorubicin / Q000008:administration & dosage; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009693:Nucleic Acid Hybridization; D009842:Oligopeptides / Q000008:administration & dosage; D043823:Taxoids / Q000008:administration & dosage; D000068878:Trastuzumab
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D009842:Oligopeptides; D043823:Taxoids; C431566:acetyl-2-naphthylalanyl-3-chlorophenylalanyl-1-oxohexadecyl-seryl-4-aminophenylalanyl(hydroorotyl)-4-aminophenylalanyl(carbamoyl)-leucyl-ILys-prolyl-alaninamide; D000077143:Docetaxel; D004317:Doxorubicin; D003520:Cyclophosphamide; D000068878:Trastuzumab