This deletion removes the l-Chicoric-acid relevant cysteine residues in HER2, disrupting the disulfide bond structure of the protein and leaving the remaining unpaired cysteine residues available for intermolecular bonding. For this reason, D16HER2 represents a constitutively active form similar to the mutated neu gene. D16HER2 transcripts have been detected in a majority of breast tumors and reported to comprise of total HER2 transcripts. Moreover, this oncogenic Imperatorin isoform has been associated with trastuzumab resistance. Transformation associated with HER2 overexpression might reflect the increase in absolute levels of this splice variant to a critical threshold for constitutive activation of HER2. Here, we describe the generation and characterization of a new reporter transgenic mouse that expresses both the human D16HER2 splice isoform and the firefly luciferase under the transcriptional control of the MMTV promoter. Analyses of these genetically engineered mice demonstrate that D16HER2 constitutively homodimerizes on the tumor cell plasma membrane and is able to transform mammary epithelium in vivo through the oncogenic properties mediated by the downstream Src kinase signaling circuitry, making this splice variant a likely candidate for the transforming form of the HER2 oncoprotein. Conversely, support for the insufficiency of wtHER2 expression alone and without additional mutations for full malignant transformation comes from the study by Finkle et al. who found that their transgenic mice developed mammary tumors in a stochastic manner and that wtHER2 expression was not confined to the tumor tissue but was also detected in morphologically normal mammary gland and in several other tissues. The key role of the cysteine residues in the HER2 juxtamembrane region has been also demonstrated by Pedersen et al., who showed that transgenic expression of a HER2 carboxyterminal fragment containing a transmembrane domain and a short extracellular region including the sequence deleted in D16HER2 led to the development of aggressive mammary tumors.