Abstract Human epidermal growth factor receptor 4 (HER4/ERBB4) belongs to the family of four receptor tyrosine kinases (HER1-4). While HER1, HER2 and HER3 are often overexpressed in breast cancer and predict poor prognosis, the role of HER4 in cancer is still unclear. Some studies suggest a tumor suppressor role of HER4, while contradictory reports suggest its oncogenic potential. HER4 gene produces multiple isoforms as a result of alternative splicing, in contrast to other members of this receptor family. We have used a gain-of-function MMTV-HER4 model isoforms, to evaluate potential developmental and carcinogenic roles of HER4-CYT1 and CYT2. Mammary gland ductal morphogenesis was significantly suppressed by expressing one of the transgene isoforms, strongly suggesting a role of HER4 in normal mammary ductal morphogenesis in addition to its role in lactation described previously. Interestingly, sustained expression of one HER4 transgene isoform resulted in formation of mammary tumor lesions, whereas no significant findings were observed in the control group. Formation of tumor lesions in these transgenic mice strongly suggests an oncogenic function of a HER4 isoform. These novel findings may help improve the rational design of targeted breast cancer therapy. Supported by NIH grant RO1 CA80065. Citation Format: Vikram B. Wali, Maureen Gilmore-Hebert, Klaus Elenius, David F. Stern. Overexpression of HER4 isoforms in transgenic mice reveal isoform-specific role in mammary gland development and carcinogenesis. abstract. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1401. doi:10.1158/1538-7445.AM2013-1401