title: Initiation of metastatic breast carcinoma by targeting of the ductal epithelium with adenovirus-cre: a novel transgenic mouse model of breast cancer.
abstract: Breast cancer is a heterogeneous disease involving complex cellular interactions between the developing tumor and immune system, eventually resulting in exponential tumor growth and metastasis to distal tissues and the collapse of anti-tumor immunity. Many useful animal models exist to study breast cancer, but none completely recapitulate the disease progression that occurs in humans. In order to gain a better understanding of the cellular interactions that result in the formation of latent metastasis and decreased survival, we have generated an inducible transgenic mouse model of YFP-expressing ductal carcinoma that develops after sexual maturity in immune-competent mice and is driven by consistent, endocrine-independent oncogene expression. Activation of YFP, ablation of p53, and expression of an oncogenic form of K-ras was achieved by the delivery of an adenovirus expressing Cre-recombinase into the mammary duct of sexually mature, virgin female mice. Tumors begin to appear 6 weeks after the initiation of oncogenic events. After tumors become apparent, they progress slowly for approximately two weeks before they begin to grow exponentially. After 7-8 weeks post-adenovirus injection, vasculature is observed connecting the tumor mass to distal lymph nodes, with eventual lymphovascular invasion of YFP+ tumor cells to the distal axillary lymph nodes. Infiltrating leukocyte populations are similar to those found in human breast carcinomas, including the presence of αβ and γδ T cells, macrophages and MDSCs. This unique model will facilitate the study of cellular and immunological mechanisms involved in latent metastasis and dormancy in addition to being useful for designing novel immunotherapeutic interventions to treat invasive breast cancer.
authors.affiliation: Tumor Microenvironment and Metastasis Program, Wistar Institute.
authors.forename: Melanie R
authors.initials: MR
authors.lastname: Rutkowski
authors.affiliation: Tumor Microenvironment and Metastasis Program, Wistar Institute.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Allegrezza
authors.affiliation: Tumor Microenvironment and Metastasis Program, Wistar Institute.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Svoronos
authors.affiliation: Tumor Microenvironment and Metastasis Program, Wistar Institute.
authors.forename: Amelia J
authors.initials: AJ
authors.lastname: Tesone
authors.affiliation: Tumor Microenvironment and Metastasis Program, Wistar Institute.
authors.forename: Tom L
authors.initials: TL
authors.lastname: Stephen
authors.affiliation: Tumor Microenvironment and Metastasis Program, Wistar Institute.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Perales-Puchalt
authors.affiliation: Tumor Microenvironment and Metastasis Program, Wistar Institute.
authors.forename: Jenny
authors.initials: J
authors.lastname: Nguyen
authors.affiliation: Department of Pathology and Lab Medicine, Perelman School of Medicine, University of Pennsylvania.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Zhang
authors.affiliation: Department of Microbiology and Immunology and Department of Genetics, Geisel School of Medicine at Dartmouth.
authors.forename: Steven N
authors.initials: SN
authors.lastname: Fiering
authors.affiliation: Division of Endocrine and Oncologic Surgery, Department of Surgery, Perelman School of Medicine, University of Pennsylvania; Rena Rowan Breast Center, Abramson Cancer Center, University of Pennsylvania; Center for Advanced Medicine, University of Pennsylvania.
authors.forename: Julia
authors.initials: J
authors.lastname: Tchou
authors.affiliation: Tumor Microenvironment and Metastasis Program, Wistar Institute; jrconejo@wistar.org.
authors.forename: Jose R
authors.initials: JR
authors.lastname: Conejo-Garcia
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000483:Alleles; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D016158:Genes, p53; D011905:Genes, ras; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology* / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic
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