Genetically defined human in mouse (HIM) model: A novel breast cancer model system that progresses in vivo and exhibits phenotypic variation

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Although human cancer cell line-derived xenografts have traditionally been the in vivo models of cancer, they typically have limited utility for predicting clinical response. Cell culture conditions for maintaining cancer cell lines impart strong selection pressures that are different from those experienced in vivo. Here, we sought to generate an in vivo model of human in mouse (HIM) by employing a unique tissue reconstitution system comprised of human breast stromal cells and epithelial organoids engineered with defined genetic elements.
 >In this HIM model, human breast epithelial organoids were isolated from mammoplasty specimen, engineered with defined genetic elements by lenti-viral infection, and reconstituted with human breast fibroblasts in cleared mouse mammary fat pads.
 >Depending on genetic elements introduced, the tissue reconstitutes gave rise to human breast tissue outgrowths ranging from hyperplasia to DCIS to invasive carcinomas. In striking contrast to the requirement of hTERT transduction for culture-based transformation assay using human mammary epithelial cells (HMECs), these primary HIM tumors exhibited spontaneous activation of endogenous telomerase. As seen in human, tumors in the HIM model system go through the multi-step tumor genesis process ranging from normal/hyperplasia, to DCIS-like, to invasive carcinoma. Consistent with the critical role of the microenvironment in human breast cancer pathobiology, HIM tumor development was highly dependent on specialized stromal fibroblasts. In addition, significant variation in histology was observed among tumors generated with the same set of genetic alterations. Preliminary clinical drug testing studies were initiated on this HIM model, and immediate response was observed upon treating HER2-driven tissue transgenic tumors with HER2 antagonist, such as Transtuzumab.
 >The HIM model provides a defined genetic and biological system in which to explore the molecular genetics of human breast cancer.