Accelerated preclinical testing using transplanted tumors from genetically engineered mouse breast cancer models.
OBJECTIVE
The use of genetically engineered mouse (GEM) models for preclinical testing of anticancer therapies is hampered by variable tumor latency, incomplete penetrance, and complicated breeding schemes. Here, we describe and validate a transplantation strategy that circumvents some of these difficulties.


METHODS
Tumor fragments from tumor-bearing MMTV-PyMT or cell suspensions from MMTV-PyMT, -Her2/neu, -wnt1, -wnt1/p53(+/-), BRCA1/p53(+/-), and C3(1)T-Ag mice were transplanted into the mammary fat pad or s.c. into naïve syngeneic or immunosuppressed mice. Tumor development was monitored and tissues were processed for histopathology and gene expression profiling. Metastasis was scored 60 days after the removal of transplanted tumors.


RESULTS
PyMT tumor fragments and cell suspensions from anterior glands grew faster than posterior tumors in serial passages regardless of the site of implantation. Microarray analysis revealed genetic differences between these tumors. The transplantation was reproducible using anterior tumors from multiple GEM, and tumor growth rate correlated with the number of transplanted cells. Similar morphologic appearances were observed in original and transplanted tumors. Metastasis developed in >90% of mice transplanted with PyMT, 40% with BRCA1/p53(+/-) and wnt1/p53(+/-), and 15% with Her2/neu tumors. Expansion of PyMT and wnt1 tumors by serial transplantation for two passages did not lead to significant changes in gene expression. PyMT-transplanted tumors and anterior tumors of transgenic mice showed similar sensitivities to cyclophosphamide and paclitaxel.


CONCLUSIONS
Transplantation of GEM tumors can provide a large cohort of mice bearing mammary tumors at the same stage of tumor development and with defined frequency of metastasis in a well-characterized molecular and genetic background.
Varticovski
Lyuba
L
Center for Cancer Research, National Cancer Institute, Frederick, Maryland. varticol@mail.nih.gov
Hollingshead
Melinda G
MG
Robles
Ana I
AI
Wu
Xiaolin
X
Cherry
James
J
Munroe
David J
DJ
Lukes
Luanne
L
Anver
Miriam R
MR
Carter
John P
JP
Borgel
Suzanne D
SD
Stotler
Howard
H
Bonomi
Carrie A
CA
Nunez
Nomelí P
NP
Hursting
Stephen D
SD
Qiao
Wenhui
W
Deng
Chuxia X
CX
Green
Jeff E
JE
Hunter
Kent W
KW
Merlino
Glenn
G
Steeg
Patricia S
PS
Wakefield
Lalage M
LM
Barrett
J Carl
JC
D000818:Animals; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D005818:Genetic Engineering; D017403:In Situ Hybridization; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation / Q000379:methods*; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction