Abstract
IntroductionEffective in vivo models of breast cancer are crucial for studying the development and progression of the disease in humans. We sought to engineer a novel mouse model of polyomavirus middle T antigen (PyV mT)-mediated mammary tumourigenesis in which inducible expression of this well-characterized viral oncoprotein is coupled to Cre recombinase (TetO-PyV mT-IRES-Cre recombinase or MIC).MethodsMIC mice were crossed to the mouse mammary tumour virus (MMTV)-reverse tetracycline transactivator (rtTA) strain to generate cohorts of virgin females carrying one or both transgenes. Experimental (rtTA/MIC) and control (rtTA or MIC) animals were administered 2 mg/mL doxycycline beginning as early as eight weeks of age and monitored for mammary tumour formation, in parallel with un-induced controls of the same genotypes.ResultsOf the rtTA/MIC virgin females studied, 90% developed mammary tumour with complete penetrance to all glands in response to doxycycline and a T50 of seven days post-induction, while induced or un-induced controls remained tumour-free after one year of induction. Histological analyses of rtTA/MIC mammary glands and tumour revealed that lesions followed the canonical stepwise progression of PyV mT tumourigenesis, from hyperplasia to mammary intraepithelial neoplasia/adenoma, carcinoma, and invasive carcinoma that metastasizes to the lung; at each of these stages expression of PyV mT and Cre recombinase transgenes was confirmed. Withdrawal of doxycycline from rtTA/MIC mice with end-stage mammary tumours led to rapid regression, yet animals eventually developed PyV mT-expressing and -non-expressing recurrent masses with varied tumour histopathologies.ConclusionsWe have successfully created a temporally regulated mouse model of PyV mT-mediated mammary tumourigenesis that can be used to study Cre recombinase-mediated genetic changes simultaneously. While maintaining all of the hallmark features of the well-established constitutive MMTV-PyV mT model, the utility of this strain derives from the linking of PyV mT and Cre recombinase transgenes; mammary epithelial cells are thereby forced to couple PyV mT expression with conditional ablation of a given gene. This transgenic mouse model will be an important research tool for identifying synthetic viable genetic events that enable PyV mT tumours to evolve in the absence of a key signaling pathway.
Highlights
Effective in vivo models of breast cancer are crucial for studying the development and progression of the disease in humans
Induction of mT-IRES-Cre recombinase (MIC) transgene expression in the mammary gland results in rapid tumour onset Polyomavirus middle T antigen (PyV mT) and Cre recombinase cDNAs were sub-cloned into a pTE vector containing an internal ribosome entry sequence (IRES) to produce a TetO-PyV MIC transgene (Additional file 1: Figure S1)
Tumour onset in the original constitutive mammary tumour virus (MMTV)-polyomavirus middle T antigen (PyV mT) model occurs with relatively short onset, with virgin females developing mammary masses with a T50 of 40 days of age [3,6]
Summary
Effective in vivo models of breast cancer are crucial for studying the development and progression of the disease in humans. Perhaps most valuable to the field of breast cancer is the widely used mouse mammary tumour virus (MMTV)driven PyV mT mouse model, in which transgene expression occurs in the mammary epithelium [3]. Mammary tumour development in this strain closely mimics the disease progression observed in humans, evolving through four distinct stages: hyperplasia, mammary intraepithelial neoplasia (MIN)/adenoma, early carcinoma and late carcinoma [4]. Another clinically relevant feature of this model is that PyV mT-induced mammary tumours are capable of metastasizing to the lungs [3]. First published two decades ago, the MMTV-PyV mT strain has since become an established tool in studying breast tumourigenesis and metastasis in vivo
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
