Overview of Genetically Engineered Mouse Models of Breast Cancer Used in Translational Biology and Drug Development

Abstract

Breast cancer is a heterogeneous condition with no single standard of treatment and no definitive method for determining whether a tumor will respond to therapy. The development of murine models that faithfully mimic specific human breast cancer subtypes is critical for the development of patient-specific treatments. While the artificial nature of traditional in vivo xenograft models used to characterize novel anticancer treatments has limited clinical predictive value, the development of genetically engineered mouse models (GEMMs) makes it possible to study the therapeutic responses in an intact microenvironment. GEMMs have proven to be an experimentally tractable platform for evaluating the efficacy of novel therapeutic combinations and for defining the mechanisms of acquired resistance. Described in this overview are several of the more popular breast cancer GEMMs, including details on their value in elucidating the molecular mechanisms of this disorder.

The past, present, and future of breast cancer models for nanomedicine development

“…The overexpression of mammary oncogenes (e.g., cyclin D1, PyMT, neu/ErbB2/ HER2, Myc, Ras, SV40 Tag, and Wnt 1) via regulatory sequences that include the mouse mammary tumor virus (MMTV) long terminal repeat (LTR) promoter (for several oncogenes such as cyclin D1, neu/ErbB2/HER2, Myc, Wnt 1 and PyMT), the whey acidic protein (WAP) promoter (for the Ras oncogene), or the 5′ flanking region of the C3(1) component of the rat prostate steroid-binding protein gene (commonly used to drive expression of the SV40 large T-antigen - C3Tag) [125] , [212] , [213] . The administration of factors such as estrogen, lactogenic hormones, or steroid hormones to engineered mice activates the oncogene in question and leads to tumorigenesis ( Table 5 ) [214] .…”

In vivomodels in breast cancer research: progress, challenges and future directions

“…introduced into the coding region of tumour suppressors such as p53 and Brca1 ). Lists of the many different breast cancer GEMMs (conventional and conditional) can be found in other recent reviews ( Pfefferle et al, 2013 ; Borowsky, 2011 ; Menezes et al, 2014 ; Dabydeen and Furth, 2014 ; Greenow and Smalley, 2015 ; Ben-David et al, 2016 ).…”

Albumin nanoparticle containing a PI3Kγ inhibitor and paclitaxel in combination with α-PD1 induces tumor remission of breast cancer in mice

“…The antitumor efficacy of Nano-PI in combination with α-PD1 treatment was evaluated in transgenic MMTV-PyMT mice with spontaneous breast cancer and lung metastasis ( 32 , 38 – 40 ). The MMTV-PyMT mouse grew 1 to 15 mammary tumor foci and developed multiple lung metastases lesions in 8 to 10 weeks.…”

“…The better efficacy of Nano-PI is a result of the enhanced delivery of both IPI-549 and PTX to macrophages in both lymph nodes and tumors, which results in complete remodeling of the immune microenvironment. Because PyMT transgenic mice with spontaneous cancer better mimic human metastatic breast cancer ( 32 , 38 , 45 ) than orthotopic or subcutaneous cancer models, the efficacy of Nano-PI and α-PD1 obtained using this model may have a better clinical translational potential and thus warrants future testing in clinical trials. In addition, because the Nano-PI formulation can be manufactured using an already established process used for Abraxane, it can be readily made available for clinical testing.…”