The development of novel therapeutics for breast cancer requires relevant preclinical models that feature organ and disease specific mutations while preserving a relevant TME. Our breast cancer tumor homografts originate from the MMTV-PyVT TG GEMM, which spontaneously develop mammary tumors. A subset of our model feature HER2 overexpression. Models can be established as standard subcutaneous or orthotopic variants, providing relevant TME and facilitating the formation of distant metastases.