Characterization of the Tet-On Grb7 and Tet-On 14-3-3sigma Mouse Models

ErbB2 is overexpressed and amplified in about 30% of all breast tumors and is correlated with poor patient prognosis. ErbB2 knock in mouse models mimic the amplification in chromosome 11 (human chromosome 17q21-25) comprising of ErbB2 and Grb7 and a deletion in chromosome 4 (human chromosome 1p35-36) including 14-3-3sigma seen in human breast cancers. Grb7 is an adaptor protein known to regulate cell migration and transcription by interacting with a cell migration protein FAK and a transcription factor protein FHL2. Grb7 overexpression has been linked to an increase in metastasis and poor patient outcome. 14-3-3sigma is negative cell cycle protein that is upregulated by p53. Interestingly, 14-3-3sigma has a role in down regulating ErbB2 expression by sequestering EGR2 from the nucleus to the cytoplasm. These results suggest that 14-3-3sigma deletion and Grb7 overexpression in ErbB2 tumors represents an interesting target to study as its deletion may be a targeted event in the development of ErbB2 tumors.;To elucidate the role of Grb7 and 14-3-3sigma I generated a mouse model utilizing the Tet-On mouse model system whereby these two proteins are overexpressed in the mouse mammary epithelium. Through this study we confirmed successful localized overexpression of both Grb7 and 14-3-3sigma in the mouse mammary gland epithelium. Further, we were able to confirm that individual expression of both Grb7 and 14-3-3sigma lead to a ductal outgrowth defect during mammary gland development. These observations confirm that Grb7 and 14-3-3sigma both play a role in mouse mammary gland development.