Mouse models of breast cancer metastasis
[1] Human breast cancer metastasizes to multiple distant organs such as the brain, lungs, bones and liver.
The classical theory developed in the early 70's anticipated that metastasis is due to genetically determined subpopulations in primary tumours.
[6] A number of discrete genetic events have to occur in order to enable individual tumor cells that have the capacity to grow at an ectopic site.
[7] The metastatic potential of sub populations within mouse mammary cells is now considered as relatively an early event and dissemination occurs at the same time of pre invasive or micro-invasive lesions.
[17] The growth of lesions at the ectopic site depends on multiple complex interactions between metastatic cells and host homeostatic mechanisms.
[18] Targeted expression of oncogenes in mouse mammary epithelial cells is a way of modeling human breast cancer.
[19] Genetic studies of common diseases in humans suffer significant limitations for practical and ethical reasons.
[22] Human cell lines can be used to model disease but it is difficult to study processes at the tissue level, within an organ or across the entire body.
[26] Transplantation of tumor cells into immunodeficient mice is a tool to study breast cancer and its metastatic effects.
After 4 weeks of development, the newly en-grafted human mammary epithelial cells expanded within the fat pad.
It harbors a regulatory DNA sequence called the long terminal repeat (LTR), which promotes steroid-hormone-inducible transcription.
[42] Whey acidic protein (WAP),[43] is another common promoter used to generate mouse mammary cancer models.
[44] MMTV-PyMT is the model of breast cancer metastasis, in which MMTV-LTR is used to drive the expression of mammary gland specific polyomavirus middle T-antigen, leading to a rapid development of highly metastatic tumors.
To check the cooperation of two oncogenes, Tim Stewert and group made the first bi-transgenic mouse models in 1987, MMTV-Myc and MMTV- Ras mice were crossed with a resulting acceleration in tumorigenesis.
[58] Ras gene can be combined with rtTA (reverse tetracycline transactivator) to generate bi-transgenic inducible mouse model through tetracycline-controlled transcriptional activation e.g. mice carrying TetO-KrasG12D (TOR) and MMTV-rtTA (MTB), comes with the transgene expressing the reverse tetracycline transactivator (rtTA) in mammary epithelial cells.
Multiple combinations and genetic modifications are made in such a way that either one or all the genes are put into a continuously expressed status, or in a controlled fashion to activate them at different time points.
Acute ablation of TGF-β signaling in MMTV-PyMT mammary tumor cells leads to a five-fold increase in lung metastasis.
The substrate luciferin, is oxidized to oxyluciferin in the presence of luciferase and emits light, which can be detected using an IVIS system such as a Xenogen machine.
Dissociated mammary cells from MMTV-PyMT: IRES: Luc; MTB (Internal ribosome entry site: Luciferin) animals (which were not exposed to doxycycline) can be injected into the lateral tail veins of immunodeficient mice on a doxycycline-free diet.
Intravital microscopy with multi photon excitation is a technique to visualize genetically engineered cells directly in vivo.
