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Accelerated Preclinical Testing Using Transplanted Tumors from Genetically Engineered Mouse Breast Cancer Models

Authors' Affiliations: ¹ Center for Cancer Research, National Cancer Institute; ² Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, ³ Science Applications International Corporation-Frederick, Inc., Frederick, Maryland; and ⁴ National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda

Requests for reprints: Lyuba Varticovski, 37 Convent Drive, Room 3060, Bethesda, MD 20892. Phone: 301-496-0498; Fax: 301-496-0497; E-mail: varticol{at}mail.nih.gov.

Purpose: 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.

Experimental Design: 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.