Novel human basal type breast cancer models generated through genetic manipulation of normal human breast tissue in mice

3873 The basal subtype of invasive carcinoma comprises 15% of human breast cancer and is associated with poor prognosis as assessed by relapse-free survival. Initially determined by gene expression profiles, basal breast cancers are now typically identified by immunohistochemistry as being ER-/HER2-/CK5+/EGFR+. In addition, it was recently observed that 15~20% of human basal breast cancers are amplified for HER2. However, no targeted therapeutic agents are available that can effectively treat the basal type breast cancer. Hence, the development of effective therapies against basal breast cancer is a major unmet medical need. To address this need, we have developed in vivo human basal type breast cancer models that recapitulate the pathogenesis of basal type human breast cancer. Through a unique combination of genetic engineering and mammary gland reconstitution, normal human breast epithelial orgnoids were transduced with combinations of oncogenic transgenes and reconstituted into human breast tissue in mice (HIM). Depending on specific gene combinations utilized, some HIM outgrowths gave rise to poorly differentiated invasive carcinomas. Immunohistochemical analysis revealed that those HIM tumors were ER-/HER2-/CK5+/EGFR+, hallmarks of basal type breast cancers in human. These HIM tumors provide attractive models to study the etiology of the basal subtype of human breast cancer and to identify effective therapies to treat this disease. For example, all basal type HIM tumors are positive for EGFR, providing an opportunity to evaluate the potential activity of EGFR inhibitors either alone or in combination in treating patients with basal type breast cancer. Despite the recent classification of HER2 amplified human basal type breast cancers, the efficacy of Herceptin on those basal breast cancers are still unknown. Since some of our basal HIM tumors are HER2-positive, they provide a model to test the effect of Herceptin in this context. These, and other similar experiments, highlight the utility of the HIM models to provide translational insight into clinical populations.